ACS Publications. Most Trusted. Most Cited. Most Read
My Activity
Recently Viewed
You have not visited any articles yet, Please visit some articles to see contents here.
CONTENT TYPES

Targeting Nuclear Receptors in Neurodegeneration and Neuroinflammation

Cite this: J. Med. Chem. 2021, 64, 14, 9592–9638
Publication Date (Web):July 12, 2021
https://doi.org/10.1021/acs.jmedchem.1c00186
Copyright © 2021 The Authors. Published by American Chemical Society
Subscribed Access
Article Views
837
Altmetric
-
Citations
-
LEARN ABOUT THESE METRICS
PDF (6 MB) OpenURL HONG KONG UNIV SCIENCE TECHLGY

Abstract

Nuclear receptors, also known as ligand-activated transcription factors, regulate gene expression upon ligand signals and present as attractive therapeutic targets especially in chronic diseases. Despite the therapeutic relevance of some nuclear receptors in various pathologies, their potential in neurodegeneration and neuroinflammation is insufficiently established. This perspective gathers preclinical and clinical data for a potential role of individual nuclear receptors as future targets in Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, and concomitantly evaluates the level of medicinal chemistry targeting these proteins. Considerable evidence suggests the high promise of ligand-activated transcription factors to counteract neurodegenerative diseases with a particularly high potential of several orphan nuclear receptors. However, potent tools are lacking for orphan receptors, and limited central nervous system exposure or insufficient selectivity also compromises the suitability of well-studied nuclear receptor ligands for functional studies. Medicinal chemistry efforts are needed to develop dedicated high-quality tool compounds for the therapeutic validation of nuclear receptors in neurodegenerative pathologies.

1. Introduction

ARTICLE SECTIONS
Jump To

Diseases associated with a loss of neuronal function such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) have a high and constantly growing global prevalence.(1,2) They span a wide spectrum of diseases leading to cognitive decline and/or disability affecting more than 40 million people in the world.(1,2) Neurodegenerative diseases are severe health burdens that massively affect quality of life and globally pressure healthcare systems and economics. In contrast to several other severe pathologies such as cancer or chronic inflammation, for which pharmacological treatment has significantly improved in the recent past, most neurodegenerative diseases lack efficient therapeutic interventions. The multifaceted neurodegenerative pathologies arise from different etiologies and disease mechanisms but still share certain common characteristics such as neuronal degeneration, loss of neuronal function, involvement of neuroinflammation, and in many cases the abnormal neuronal disposal of certain proteins.
Dementia including AD has a global prevalence of 5–7% in people above the age of 60 years(1,3) with 36 million patients in 2010 and an alarming estimated number of 115 million patients in 2050.(1) Despite these enormous numbers, current options for dementia treatment are almost negligible. For example, acetylcholinesterase inhibitors and memantine show only limited symptomatic effects(4,5) in early disease stages, and efficacy of ginkgo biloba could not be demonstrated, yet.(6) So far, no therapeutic intervention is available which counteracts underlying disease mechanisms.(7) Tau directed agents are immature,(8) and amyloid-β (Aβ) targeting therapies have failed in clinical development.(9) As a consequence of several recent drawbacks, research on pharmacological agents for dementia treatment has significantly decreased.(10) Improved understanding of the complex underlying pathomechanisms(11) and the search for new molecular targets to counteract AD and other forms of dementia are hence imperative. Therein, particularly regenerative strategies are urgently needed.(10)
PD, which mainly arises from degeneration of dopaminergic neurons in the substantia nigra due to deposition of α-synuclein and other toxic factors,(12) has an estimated prevalence of 1.0% in people above the age of 60.(13) Its pathology and disease mechanisms are better defined than in AD, and therapeutic options, which include, for example, dopaminergic agents, monoamine oxidase inhibitors, catechol-O-methyl transferase inhibitors, NMDA antagonists, and anticholinergics,(14) are somewhat more effective. Still, available therapeutic interventions for PD only address disease symptoms without affecting the underlying causes as well, and research on disease-modifying interventions that delay progression or even provide a cure was characterized by several recent failures, too.(15) Hence, new strategies to reverse the disease are urgently needed in PD.
MS is the most prevalent disabling disease in younger people and affects approximately 3 million people in the world.(16) An autoimmune destruction of neuronal myelin sheaths and constant neuroinflammation are the central factors in MS leading to progressive neuronal damage. The treatment of MS has markedly evolved over the last decades(17) allowing a significantly slowed progression with modern therapeutic interventions in several cases.(16,17) However, the multiple available MS treatment options target the immune system to counteract inflammatory processes and consequently prevent neuronal destruction.(18) Despite the remarkable progress achieved by the new MS medications, therapeutic interventions to reverse MS are urgently required.(18)
Several lines of evidence present certain nuclear receptors as potential molecular targets to treat neurodegenerative diseases. As ligand-sensing transcriptional regulators, nuclear receptors control metabolic homeostasis and have multiple cell-protective functions against toxic metabolites. Hence, a potential neuroprotective role of these transcription factors is obvious. Moreover, nuclear receptors are involved in the control of cell proliferation, differentiation, and survival, suggesting their modulation also as potential avenue to regenerative approaches. Putative strategies for regenerative treatment in neurodegenerative diseases may target neuronal protection and repair mechanisms. Therapeutic strategies which are able to promote neuronal regeneration, restore neuronal integrity, and counteract neuroinflammation would hold enormous potential for numerous diseases associated with neurodegeneration. Although the adult human brain is one of the organs with the lowest regenerative ability, neurogenesis occurs throughout life from neural stem cells (NSCs),(19) and knockout studies have already revealed certain growth factors and their downstream signaling pathways, transcriptional regulators, and epigenetic proteins as important mediators in neuroregeneration.(19) Putative novel therapeutic approaches to neurodegenerative diseases might target these regulatory proteins to modulate survival, proliferation, differentiation, or migration of NSCs. In addition to NSCs, which may open a general avenue to regenerative effects, other neuronal cell types hold regenerative potential in the various pathologies. Oligodendrocytes (OLs), for example, play a key role in myelination, and considerable efforts have been spent on identifying mechanisms that promote remyelination by OLs in MS.(18) This perspective gathers preclinical and clinical evidence for the potential of nuclear receptors(20) as future molecular targets in the treatment of neurodegenerative pathologies and focuses on the current stage of medicinal chemistry to target these transcriptional regulators as new avenues for a cure in neurodegenerative diseases.

2. Nuclear Receptors and Neurodegeneration

ARTICLE SECTIONS
Jump To

The protein family of nuclear receptors (NRs) in humans comprises 48 members (Figure 1a) that act as ligand-sensing transcription factors and regulate gene expression profiles upon changes in ligand concentrations.(21) As their key function, NRs translate stimuli by signal molecules—e.g., hormones or lipid mediators—into enhanced or decreased expression of certain sets of genes. However, the cellular functions of NRs are multifaceted (Figure 1b,c) and include direct and indirect genomic effects, for example, by interacting with other transcription factors (tethering, transrepression, Figure 1c), as well as nongenomic activities. The complex roles and network of NRs involve multiple regulatory mechanisms (reviewed in, e.g., refs (22−25)) such as ligand-dependent and -independent regulation, post-translational modifications (phosphorylation and SUMOylation) which can be activating or inhibiting, ligand effects on subcellular localization, NR monomer–dimer–oligomer equilibria, and a network of coregulators that are recruited or released upon ligand binding.(26) Most NRs share a typical common architecture of an N-terminal ligand-independent activation function 1 (AF-1) followed by the DNA binding domain (DBD) and a C-terminal ligand binding domain (LBD), the latter of which recognizes the ligand and undergoes conformational changes upon ligand binding.(27,28) These changes often affect the structure and position of the so-called ligand-dependent activation function 2 (AF-2), which is located in the C-terminal helix (H12) of the LBD. Ligand chemotype recognition varies remarkably between different NRs, enabling selective NR modulation by small molecule ligands and rendering NRs as attractive targets for a pharmacological modulation of gene expression.(21,26) About half of the NR family is well studied and has pharmacological relevance. Endogenous ligands of these receptors are known, and several potent and selective small molecule modulators are available to determine their roles in health and disease. For other NRs, available knowledge on ligands, biochemical function, and interaction networks as well as pathological relevance is limited, and for several so-called orphan NRs,(29) endogenous ligands remain elusive. Some nuclear receptors are considered as potentially attractive pharmacological targets in the context of neurodegeneration based on varying levels of evidence. In the following, we summarize findings pointing to an involvement of individual NRs in neurodegeneration, neuroprotection, and neuroinflammation, and discuss the potential and limitations of their available ligands.

Figure 1

Figure 1. Nuclear receptors. (a) Overview over the nuclear receptor superfamily comprising 48 members in human.(30) (b) Basic mechanism of genomic nuclear receptor function. NRs of the NR1 family like LXRs and PPARs bind to their specific NRE within the promoter region of their target genes as obligate heterodimers with RXR. In the absence of ligand binding, these heterodimers associate with corepressor complexes, which results in repression of transcription. Conformational changes of the complex occur upon ligand binding, which involves displacement of the corepressor complex and subsequent coactivator recruitment, resulting in the transcription of target genes. (c) Exemplified indirect genomic action of nuclear receptors. For example, NFκB-regulated pro-inflammatory genes are differently controlled by NRs. Monomers such as PPARγ or LXR can undergo SUMOylation upon ligand binding and recruit corepressors to inhibit gene expression via NFκB (p50 and p65 subunits) interaction with its response elements.

2.1. Peroxisome Proliferator-Activated Receptors (PPAR, NR1C)

2.1.1. Overview

The three peroxisome proliferator-activated receptors PPARα, PPARγ, and PPARδ (also termed PPARβ) are cellular lipid sensors and considered as master regulators of lipid and glucose homeostasis.(31) While the PPARs are differentially expressed in peripheral tissues with PPARα as the major hepatic isoform, PPARγ in adipose tissue and immune cells, and ubiquitous expression of PPARδ, all three subtypes are found in the brain with the highest levels in neurons.(32) PPARs are activated by various nutritional and endogenous lipids such as polyunsaturated fatty acids, vitamin E metabolites, and fatty acid mimetic molecules.(31,33−35) The PPARα and PPARγ isoforms have a long history as drug targets in metabolic diseases (PPARα: hyperlipidemia, PPARγ: type 2 diabetes), but relevance of fibrates (PPARα agonists), glitazones (PPARγ agonists) and glitazars (dual PPARα/γ agonists) for these indications has declined.(31,36) Preclinical evidence ascribes all three PPARs therapeutic potential in a number of neurodegenerative pathologies, and interest of drug discovery and pharmacology in the PPARs remains high.

2.1.2. PPARs in Alzheimer’s Disease

In AD, evidence for therapeutic potential is mainly available for PPARγ activation. Observational studies in patients receiving antidiabetic medication point to a protective role of PPARγ activation.(37−39) In several large cohorts, treatment with the PPARγ agonist pioglitazone (1) decreased the risk of developing dementia.(37−39) Additionally, some nonsteroidal anti-inflammatory drugs (NSAIDs) were found to reduce the risk for AD, which might be associated with the PPARγ agonistic component of these drugs.(2,40) The therapeutic potential of PPAR activation in AD-related pathologies is rationalized by PPAR-mediated reduction of Aβ and tau burden, anti-inflammatory activities, and protective effects on mitochondria.(2,41) Numerous preclinical studies have observed beneficial effects in AD-related models. For example, PPARγ activation caused upregulation of insulin-degrading enzyme in primary neurons from rats and AD model mice, a protease which is also able to degrade Aβ.(42,43) Additionally, PPARγ activity was found to decrease expression of β-secretase, which cleaves amyloid precursor protein (APP) to produce Aβ.(43−45) PPARγ activation with pioglitazone (1) in rats,(46) in double transgenic APP/PS1 mice,(47) and in triple transgenic AD mice(48) reduced Aβ levels in the central nervous system (CNS) and improved energy homeostasis, whereas the irreversible PPARγ antagonist GW9662 (2) caused the opposite effect.(49) Congruently, several studies(50,51) report reduced memory deficits in APP/PS1 mice upon pioglitazone (1) treatment, while intraventricular administration of the PPARγ antagonist GW9662 (2) caused motor dysfunction.(49) In APP/PS1 mice, pioglitazone (1) was also remarkably effective in clearing Aβ, decreasing neuroinflammation, and improving cognitive function when administered in a short-term fashion after disease onset.(52) Similar improvements of cognitive deficits upon pioglitazone (1) treatment were observed in double transgenic mice expressing mutant human APP and a constitutively active form of transforming growth factor-β1 (TGF-β1) but without effects on Aβ burden.(53) In rats receiving an intracerebroventricular Aβ injection to establish an AD model, pioglitazone (1) improved cognitive function, reduced neuroinflammation, and reversed oxidative mitochondrial damage.(54) PPARγ antagonist treatment counteracted the beneficial effects of pioglitazone (1). Pioglitazone (1) was also found to improve synaptic function in APP/PS1 mice in a pathway involving cyclin-dependent kinase 5 (cdk5).(51) Moreover, pioglitazone (1) and troglitazone reduced tau protein levels and tau aggregation in cellular models and in primary neurons, while GW9662 (2) reversed these effects.(55,56) Accordingly, four months of treatment with pioglitazone (1) and rosiglitazone (3) attenuated tau hyperphosphorylation in triple transgenic AD mice.(48)
Despite the mostly promising preclinical observations, late-stage clinical trials with the PPARγ agonist rosiglitazone (3) failed to reveal a clinical benefit in the treatment of mild-to-moderate AD.(57,58) Meta-analyses of the reported small and larger clinical trials on pioglitazone (1) and rosiglitazone (3) in AD came to the conclusion that based on the available data rosiglitazone (3) has no benefit in mild-to-moderate AD, while pioglitazone (1) might have some efficacy.(59,60)

2.1.3. PPARs in Parkinson’s Disease

Protective effects of PPAR activation in PD have also been reported from numerous preclinical models with a focus on the PPARγ agonistic thiazolidinediones. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, pioglitazone (1) prevented microglial activation and loss of dopaminergic neurons,(61) restored tyrosine hydroxylase (TH) levels,(61) and improved motor impairments.(62) A potential involvement of monoamine oxidase B inhibition(62) in these effects of pioglitazone (1) is speculated. Rosiglitazone (3) exhibited anti-inflammatory effects in MPTP-induced PD in mice, too, and reverted microglial activation as well as pro-inflammatory cytokine levels.(63) Pioglitazone (1) was even examined in MPTP-induced PD in rhesus monkeys, where it also normalized TH levels and other CNS markers of PD. Concomitantly, pioglitazone (1) administration (5 mg/kg p.o. daily) caused a marked improvement in several behavioral tests compared to placebo-treated animals including performance in fine motor skills.(64) Even in a rare and severe model of late-stage PD in mice induced by mitochondrial complex IV defects in dopaminergic neurons, which is characterized by extensive loss of dopaminergic neurons and strong motor deficits, pioglitazone (1) exhibited improvements in motor impairment and neuroinflammation.(65)
In addition to the glitazones, neuroprotective and anti-neuroinflammatory effects in the rodent MPTP model were also observed upon treatment with the non-thiazolidinedione PPARγ (partial) agonists MDG548(66,67) or LSN862,(68) which further corroborates involvement of PPARγ modulation in therapeutic effects. Moreover, treatment of lipopolysaccharide (LPS)-stimulated primary mouse microglia with MDG548 revealed increased phagocytic activity as another potential mechanism of PPAR-mediated beneficial effects in neurodegenerative diseases.(67)
Similar to PPARγ agonists, the PPARα agonist fenofibrate, the structurally related PPARδ agonists GW0742 (4) and GW501516 (5), and the dual PPARα/γ agonist MHY908 ameliorated MPTP-induced PD in mice with cognitive and locomotor improvements, reduced TH levels, decreased neuroinflammation, and less neuronal damage in several studies.(69−74) In line with this, PPARδ antagonist (GSK0660) treatment worsened the toxicity of 1-methyl-4-phenylpyridinium iodide (MPP+) on neuronal cells in vitro, while the agonist GW0742 (4) reversed this effect.(72) Neuron-specific knockout of PPARγ and/or PPARδ in the MPTP-induced model of PD did, however, not result in more severe neuronal damage, potentially suggesting that PPAR in other cell types is important for the protective effects observed with PPAR agonists.(75) In the less common rotenone-induced rat model of PD, which has a strong endoplasmic reticulum stress component, intracerebroventricular infusion of PPARδ agonist GW501516 (5) improved locomotor activity, decreased endoplasmic reticulum stress, reduced neuronal apoptosis, and counteracted the loss of dopaminergic neurons.(76)
PPAR ligands were also examined in the 6-hydroxy dopamine (6-OHDA)-induced rodent model of PD. Pioglitazone (1) decreased mortality, ameliorated microglial activation and reduced NFκB activity, enhanced neuronal survival, and improved locomotor deficits in 6-OHDA treated rats.(77,78) Similarly, intraperitoneal administration of rosiglitazone (3) to 6-OHDA rats restored TH levels, prevented microglial activation, and decreased pro-inflammatory markers such as cyclooxygenase-2 (COX-2) and tumor necrosis factor α (TNFα) in the CNS.(79) Since the beneficial effects of rosiglitazone (3) were strengthened when the drug was administered before disease induction, a potential involvement of decreased COX-2 activity in the neuroprotective effects is speculated.(79) In an extended 6-OHDA rat model with concomitant chronic levodopa administration, rosiglitazone (3) was also found to attenuate levodopa-induced dyskinesia.(80)
A recent in vitro study provided a link between PPARs and Nurr1 (see section 2.7.2) activity.(81) A PPAR response element is located in the promoter region of the neuroprotective transcription factor Nurr1, and the PPARα agonist gemfibrozil enhanced Nurr1 expression in wild-type but not in PPARα knockout dopaminergic neurons and mice.
In line with the promising neuroprotective activities of PPARγ agonists in preclinical models of PD, a retrospective study has revealed protective effects of glitazone(82) intake. Incidence of PD was reduced in patients receiving a thiazolidinedione as antidiabetic medication compared to other antidiabetic drugs. Previous thiazolidinedione use was not protective,(82) and no protective effect was observed for fibrate use.(83)

2.1.4. PPARs in Multiple Sclerosis

In MS patients, a significant upregulation of PPARγ has been detected in cerebrospinal fluid (CSF).(84) PPARγ levels additionally correlated with the number of immune cells and IgG index in CSF as neuroinflammatory markers.(84) PPARα, PPARδ, and the key PPAR coactivator PGC-1α were below the detection limit and hence not considered as elevated.(85) A recent study(86) reported strong downregulation of PPARγ but not PPARα or LXRα/β in macrophages derived from MS patients compared to healthy controls. Moreover, treatment of macrophages from healthy donors with the MS-associated pro-inflammatory cytokines interferon γ (IFNγ) and interleukin-1 β (IL-1β) resulted in a similar downregulation of PPARγ.
In line with these findings, considerable preclinical evidence for the therapeutic potential of PPAR agonism in MS has accumulated and mainly suggests the PPARγ subtype as a promising target. Multiple studies have demonstrated that PPARγ activation by pioglitazone (1)(87−89) or 15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ2)(90) treatment ameliorates experimental autoimmune encephalomyelitis (EAE), and, expectedly, dual treatment with 15d-PGJ2 and RXR agonist 9-cis retinoid acid (9-cis RA, 43) achieved enhanced efficacy.(91) Mechanistically, these effects of PPARγ activation are hypothesized to involve protective effects on mitochondria, enhanced OL differentiation, anti-inflammatory effects on phagocytic macrophages and microglia, and modulation of T cell differentiation.
In cellular setting, pioglitazone (1) or docosahexaenoic acid (45) activated PPARγ in oligodendrocyte progenitor cells (OPCs) to promote their maturation. The effect was blocked by the PPARγ antagonist GW9662 (2). PPARγ activation also counteracted the TNFα-induced arrest of OPCs in a pathway putatively involving phosphorylation of extracellular signal kinases (ERKs).(92) Moreover, PPARγ agonists were found to protect OLs against inflammatory damage to mitochondria.(93) Inflammatory stimuli with TNFα cause enhanced superoxide production by mitochondria and decreased membrane potential. Pioglitazone (1) counteracted these effects and promoted PGC-1α expression, which increases the biogenesis of mitochondria.
Treatment of primary mouse microglia with PPARγ agonists (15d-PGJ2, pioglitazone (1), rosiglitazone (3), ciglitazone) prevented LPS- or cytokine-induced NO production, IL-1β release, and IL-6 release.(94) Similar effects were observed in primary mouse astrocyte cultures(94) and in primary rat Schwann cells.(95) A recent study demonstrated the importance of the PPARγ-regulated fatty acid translocase CD36 in clearance of myelin debris by phagocytes and suppression of neuroinflammation.(96) Through enhanced CD36-mediated myelin uptake, phagocytic macrophages and microglia adopted a less inflammatory phenotype. Inhibition of CD36 promoted neuroinflammation in EAE. In line with this, Wouters et al.(86) detected increased PPARγ signaling in macrophages upon myelin phagocytosis—potentially induced by fatty acids contained in myelin debris—which was blocked by GW9662 (2). PPARγ expression was not altered by myelin uptake. Vice versa, the PPARγ antagonist GW9662 (2) did not affect myelin phagocytosis but disturbed intracellular lipid processing.
In T cells, PPARγ activation was found to act as a negative regulator of differentiation to Th17 cells in a pathway involving TGF-β, IL-6, and RORγt.(88) The PPARγ agonists pioglitazone (1), ciglitazone, and GW347845 reduced proliferation and pro-inflammatory cytokine secretion in a T cell line (Jurkat) and in phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 MS patients and 12 healthy donors.(97) In EAE, pioglitazone (1) treatment selectively reduced Th17 but not Th1 differentiation.(88) Th17 cell differentiation was also reduced by treatment with an endogenous PPARγ activator (13s-HODE).(88) T cell-specific PPARγ knockout had the opposite effect, strongly enhanced Th17 cell differentiation, and caused an earlier disease onset in EAE.(88) Notably, pioglitazone (1) treatment of T cells from healthy donors or MS patients also reduced the number of IL-17 producing T cells formed upon TGF-β/IL-21 stimulation.(88) PPARγ is hence speculated to regulate autoimmunity in the CNS by controlling T cell differentiation.(88)
Some studies also point to a potential of PPARδ in MS. Treatment with the PPARδ agonist GW0742 (4)(98) had therapeutic efficacy in EAE, and PPARδ-deficient mice displayed prolonged disease duration in EAE with compromised remission and recovery.(99) Therein, PPARδ knockout animals revealed elevated INFγ and IL-17 levels in the brain and alterations in T cell populations. In an in vitro model of demyelination and neuroinflammation using embryonal rat neuronal cells and antibodies against myelin oligodendrocyte glycoprotein (MOG), PPARδ agonist GW501516 (5) exhibited anti-inflammatory effects but failed to counteract demyelination-induced changes in gene expression.(100) In MOGp35-55-induced EAE in mice, PPARδ activation (with GW501516 (5) or L165041 (6)) counteracted IFNγ and IL-17 production by T cells and lowered levels of other pro-inflammatory cytokines in the CNS.(101) PPARδ activation is therefore speculated to have anti-inflammatory effects in MS and might be involved in remission and recovery of MS-associated pathology. In line with this, treatment of human OLs or primary mouse OLs with the nonselective PPAR agonist gemfibrozil promoted differentiation and enhanced expression of myelin-related genes.(102,103) In primary mouse OLs, the effect was lost in cultures from PPARδ-deficient animals but not in cells lacking PPARα.(102)
On the basis of accumulating evidence for the therapeutic potential of PPARγ activation in MS, pioglitazone (1) was studied in some small clinical trials. In a one-year, placebo-controlled trial, pioglitazone (1) use was safe in relapsing remitting MS.(104) The study discovered a reduction in gray matter atrophy and a tendency to decreased lesion burden, while no improvement in the expanded disability status scale was observed.(104) Another small study suggested that pioglitazone (1) treatment may reduce lesion development in relapsing remitting MS.(105) In a cohort study(106) with MS patients also affected by the metabolic syndrome, treatment with either of the antidiabetic drugs metformin and pioglitazone (1) over 6 months resulted in a decreased number of lesions compared to untreated patients. Both drugs also had anti-inflammatory effects as observed by lower cytokine secretion. This limited evidence for therapeutic efficacy of pioglitazone (1) in MS is encouraging, but larger and longer trials would be needed to demonstrate a clinical benefit. Moreover, it may be doubted whether poorly CNS available pioglitazone (1) is a good choice in this indication since PPARγ activation in the brain appears to mediate the desired anti-inflammatory and neuroprotective effects.

2.1.5. PPAR Ligands

In the past, the PPARs have been in the focus of drug discovery for their involvement in metabolic balance and their potential as drug targets for highly prevalent metabolic diseases.(36) Extensive efforts were made to develop various types of PPAR ligands (Scheme 1). Numerous subtype selective and nonselective ligands target one, two, or all three PPARs. Elafibranor (7)(107) activates PPARα and PPARδ, farglitazar (8)(108−110) is an example of a potent dual PPARα/γ agonist, L796449 (9)(111) is a dual PPARγ/δ agonist, and GW9578 (10)(112) is a balanced pan-PPAR agonist. Achieving subtype selectivity among the PPARs is not trivial, but several potent subtype selective agonists have been developed. GW7647 (11),(112) CP-775146 (12),(113) and NS-220 (13, also termed LS-191458)(114) are potent and selective PPARα agonists. In past studies, Wy-14643 (14)(115) was used as PPARα agonist but later found to activate PPARγ(116) and RXRs(117) as well. For PPARγ, the drug approved thiazolidinediones rosiglitazone (3)(118) and pioglitazone (1),(119) GW1929 (15),(120) and 16(121) comprise high potency and strong subtype selectivity. In addition, the covalent, irreversible PPARγ antagonist GW9662 (2)(122) is a very valuable tool to study PPARγ biology. L165041 (6),(111) GW501516 (5),(123,124) GW0742 (4),(124) and seladelpar (17)(125) are the most selective PPARδ activators with high potency. Since the majority of PPAR agonists comprise acidic, fatty acid mimetic structures,(34) their CNS availability is limited, however. Several preclinical studies have hence applied the PPAR agonists via intracerebroventricular infusion.(74) Pioglitazone (1), the most widely used PPARγ agonist in studies and trials on neurodegenerative diseases, presents poor CNS availability mainly due to P-glycoprotein (P-gp) efflux.(126) GSK1997132B (18)(127) has been specifically developed as a brain-penetrant (partial) PPARγ agonist.

Scheme 1

Scheme 1. Selected PPAR Ligands Used in Studies on Neurodegeneration or with Preferable Tool Compound Characteristics

2.1.6. Conclusion

Overall, activation of PPAR, especially the PPARγ subtype, has been found to exhibit attractive effects in multiple in vitro and in vivo models of neurodegenerative diseases (summarized in Table 1), but translation toward therapeutic efficacy in humans is lacking. This may be due to a merely protective rather than therapeutic role of PPAR agonism, which aligns with observations that the use of pioglitazone (1) as an antidiabetic medication reduced AD risk and PD incidence. It may also be speculated that the glitazones, which were used in the majority of preclinical studies on neurodegeneration but have poor CNS bioavailability, exhibited most of their effects through peripheral rather than CNS activity. PPAR ligands specifically designed for blood–brain barrier (BBB) penetration are needed to further validate PPAR activation as a therapeutic approach in neurodegeneration. Additionally, the beneficial effects observed with glitazones require confirmation with other PPAR agonist scaffolds to exclude involvement of other, non-PPAR-mediated mechanisms.
Table 1. Summarized Observations on PPARs in Neurodegeneration
PPARα (= NR1C1), PPARδ (= NR1C2; also known as PPARβ, NUC1, and FAAR), and PPARγ (= NR1C3)
PPARs in ADPioglitazone (1) use reduced AD risk in cohort studies.(37−39)
PPARγ activation induces insulin-degrading enzyme which can degrade Aβ.(42,43)
PPARγ activation downregulates β-secretase which cleaves APP to produce Aβ.(43−45)
PPARγ activation decreased memory deficits(50,51) and reduced Aβ(46−48) and tau(48) levels in rodent models of AD.
PPARs in PDPPAR activation prevented microglial activation and loss of dopaminergic neurons, restored tyrosine hydroxylase (TH) levels, and improved motor impairments in rodent models of PD (PPARα,(69−74) PPARγ,(61−65,77−80) PPARδ(69−74)).
Incidence of PD was reduced in patients receiving pioglitazone (1) as an antidiabetic medication.(82) Fibrate use had no such effect.(83)
PPARs in MSPPARγ but not PPARα and PPARδ was found upregulated in CSF of MS patients.(84,85)
PPARγ but not PPARα and LXR was found downregulated in macrophages from MS patients.(86)
PPARγ activation ameliorated EAE.(87−90)
PPARδ activation ameliorated EAE,(98) and PPARδ knockout compromised recovery from EAE.(99)
PPARγ activation reduced inflammatory response of PBMCs from healthy donors and MS patients.(97)
PPARγ activation prevented arrest of OPCs(92) and protected OLs against inflammatory damage.(93)
PPARγ activation induced CD36 to enhance myelin debris clearance.(96)
Pioglitazone (1) treatment reduced number of lesions and gray matter atrophy in MS patients.(104−106)

2.2. RevERB (NR1D)

2.2.1. Overview

Recent data also point to a potential involvement of the transcriptional repressors reverse ERB (revERBα, NR1D1; revERBβ, NR1D2) in neurodegenerative pathologies.(128,129) These proteins participate in the circadian clock as repressors and are considered as counterparts/antagonists of the retinoic acid receptor related orphan receptors (RORs).(129,130) RevERBα is encoded by the opposite DNA strand of the thyroid hormone receptor α (THRα, also termed ERBA oncogene) explaining the unusual name of the nuclear receptor.(129,131) RevERBs act mainly as monomers and lack the typical C-terminal AF-2 of NRs providing a first hint to their transcriptional repressor activity.(132,133) Accordingly, revERBs strongly recruit corepressors such as NCoR, resulting in chromatin condensation and gene repression.(134) Expression of revERBs varies in a circadian fashion.(135,136)

2.2.2. RevERB in Neuroinflammation

A number of preclinical studies have revealed promising effects of revERB modulation in neuroinflammation and neurodegeneration, but the reported observations are also controversial. In vitro, effects of treatment with the revERB agonist SR9011 (19) were analyzed in primary microglia from neonatal rats.(137) The compound diminished pro-inflammatory cytokine release upon TNFα treatment and decreased phagocytic activity. Mitochondrial activity and ATP generation as well as expression of genes involved in carbohydrate metabolism were also reduced. Guo et al.(138) found beneficial effects of pharmacological revERBα activation with GSK4112 (20) and SR9011 (19), which dose-dependently counteracted LPS-induced microglial activation in the murine microglial cell line BV2, in primary mouse microglia, and in mice. The observed anti-inflammatory effects of revERBα activation involved NFκB-dependent pathways and a decreased release of pro-inflammatory cytokines.

2.2.3. RevERB in Alzheimer’s Disease

Similarly, the revERB activator SR9009 (21) counteracted cognitive dysfunction and decreased cortical Aβ levels in the SAMP8 mouse model of AD.(139) Additionally, revERB activation enhanced the number of synapses and upregulated marker proteins of synaptic health, which are decreased in the disease model. In line with these findings, Griffin et al.(140) showed that revERBα knockout enhanced microglial activation in vivo with spontaneous inflammation in the hippocampus, and revERBα knockout mice revealed a markedly increased neuroinflammatory reaction to LPS. As in other studies, these effects were linked to altered NFκB signaling. In vitro, cultured revERBα-deficient primary microglia exhibited a pro-inflammatory phenotype, and a coculture model revealed increased neuronal death for revERBα-deficient microglia. Somewhat contradictory to these encouraging observations for pharmacological revERB activation, Lee et al.(141) discovered beneficial effects in neurodegeneration upon inhibition of revERB activity. RevERB knockdown or inhibition with the antagonist SR8278 (22) in the 5XFAD model of AD in mice enhanced Aβ uptake by microglial cells and decreased size and number of Aβ plaques.

2.2.4. RevERB in Multiple Sclerosis

Chang et al.(130) probed the role of revERB in EAE and observed anti-inflammatory activity of the transcription factor in Th17 cells. RevERB antagonized RORγt, which regulates expression of IL-17 to drive inflammation. RevERB overexpression or treatment with revERB activator SR9009 (21) remarkably ameliorated EAE in mice and suppressed disease progression. At the same time, Chang et al. also observed milder EAE in revERB-deficient mice, however, which appeared to be due to disturbed T cell differentiation to Th17 cells. Hence, despite being promising, the findings on revERB modulation in neurodegenerative and neuroinflammatory pathologies are inconsistent.

2.2.5. RevERB Ligands

In the recent decade, considerable knowledge on revERB ligands has been obtained (summarized in a recent review(128)). Heme was found as a natural revERB ligand(142) and constitutes the first endogenous nuclear receptor ligand which is not a hormone, steroid, or lipid. Medicinal chemistry has provided a number of revERB modulators as useful tool compounds (Scheme 2). GSK4112 (20) is the prototype of the most widely used revERB agonists, and several descendants (19, 2126) of this chemotype with enhanced potency and improved properties were developed.(128,129) Within this series, GSK2945 (23) provides the most preferable profile with high revERB agonist activity (EC50 0.05 μM), sufficient selectivity, and a pharmacokinetic profile suitable for in vivo studies.(143) In addition, two further revERB agonist chemotypes have been described,(144,145) exemplified by 27 and 28, which are highly active examples of each series with sub-micromolar potencies. Development of revERB antagonists was not as successful as for agonists. SR8278 (22) with an IC50 value of 0.47 μM is the most potent tool to date.(128,129,146) Two further weak revERB antagonist scaffolds (29, 30)(147,148) have been recently described and provide a solid basis for the development of improved tools to study revERB biology.

Scheme 2

Scheme 2. RevERB Modulators

2.2.6. Conclusion

Despite some promising observations (summarized in Table 2), available data on revERB in neurodegeneration are limited and contradictory since beneficial effects were observed for both knockout/inhibition and overexpression/activation. Consistent understanding of the transcription factor’s role in neurodegeneration is lacking, and further research is required to validate revERB as a therapeutic target. Additional and improved tool compounds to study pharmacological revERB modulation will be needed since the revERB activators GSK4112 (20), SR9009 (21), and SR9011 (19) that were used in most experiments share a common chemotype and are likely to share common off-targets. Accordingly, a recent report(149) suggests revERB-independent effects of SR9009 (21). Validation of revERB would strongly benefit from a set of structurally diverse modulator scaffolds to exclude off-target effects in a chemogenomic fashion. RevERB modulator development should also consider the CNS as attractive site of action and provide BBB penetration data. In addition, the majority of studies on revERB in neurodegeneration have been conducted without important control experiments such as revERB knockdown to validate revERB-mediated effects. Future studies would profit from considering the unclear specificity of revERB ligands and a design comprising control experiments to demonstrate involvement of revERB modulation in therapeutic effects.
Table 2. Summarized Observations on revERB in Neurodegeneration
RevERBα (= NR1D1; also known as EAR1) and revERBβ (= NR1D2; also known as EAR1β, BD73, RVR, and HZF-2)
RevERB in neuroinflammationRevERBα knockout in mice enhanced microglial activation and neuroinflammatory reaction to LPS.(140)
RevERB activation counteracted microglial activation(138) and pro-inflammatory cytokine release.(137)
RevERB in ADRevERB knockout or inhibition enhanced microglial Aβ uptake and decreased the size and number of Aβ plaques in 5XFAD mice.(141)
RevERB activation decreased cognitive dysfunction and cortical Aβ levels in a rodent AD model.(139)
RevERB in MSRevERB knockout caused milder EAE.(130)
RevERB overexpression or activation ameliorated EAE and suppressed disease progression.(130)

2.3. Liver X receptors (LXRs)

2.3.1. Overview

The liver X receptors (LXRs)(150) act as key regulators of cholesterol homeostasis and as such control, for example, the expression of the cholesterol transporters ATP-binding cassette transporter A1 (ABCA1) and ABCG1 as well as the apolipoproteins ApoE and ApoC. Additionally, LXR activation exhibits anti-inflammatory effects. The receptors are endogenously activated by oxysterols (oxidized cholesterol derivatives) such as 24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol, the latter of which is also found in the brain with high abundance and hence also termed cerebrosterol.(151,152) The two LXR subtypes (LXRα, NR1H2; LXRβ, NR1H3)(150) are structurally conserved but differ in their expression patterns. LXRα is found at high levels in liver, intestine, adipose tissue, and macrophages, while LXRβ is ubiquitously expressed. The therapeutic potential of LXR modulation in neurodegeneration is mainly attributed to three general mechanisms, the regulation of (CNS-)cholesterol homeostasis, anti-inflammatory effects, and involvement in Aβ elimination in AD.(152−155)

2.3.2. LXR, Cholesterol, and Neuronal Health

Approximately one-fourth of the body’s cholesterol content is found in the CNS where it is a key component of myelin sheaths and neuronal cell membranes illustrating the importance of cholesterol homeostasis in the brain.(156−158) Most of the CNS cholesterol content arises from de novo synthesis—mostly by astrocytes—which as cholesterol transport and degradation is tightly regulated by LXRs.(152,159) LXR agonists were found to promote the cholesterol supply from astrocytes to neurons via induction of the cholesterol transporters ABCA1 and ABCG1 mediating cholesterol efflux and via upregulation of ApoE for cholesterol transport to neurons.(159,160) LXR activity hence appears crucial for neuronal health, and several knockout studies support this hypothesis. While LXRα knockout mainly impairs peripheral cholesterol homeostasis,(161) LXRβ-deficient mice at seven months of age developed neuronal lipid accumulation, degeneration of motor neurons, and axonal atrophy resulting in an amyotrophic lateral sclerosis-like phenotype.(162,163) Double knockout of both LXR subtypes in mice led to impairment in spatial learning and motor coordination which was associated with thinner myelin sheaths in the cerebellum.(164) Expression levels of the myelin components myelin basic protein and proteolipid protein as well as ABCA1 were decreased in these animals.(164) Knockout of LXRβ also caused neurodegeneration of the optic nerve and in retinal ganglia, and was associated with increased deposition of Aβ in ganglion cells, while LXRα-deficient mice did not show such characteristics.(165)

2.3.3. LXR in Alzheimer’s Disease

Most efforts in studying LXRs in neurodegeneration focused on aspects of AD. Anti-inflammatory effects of LXR activation were found to be beneficial in several in vitro and in vivo studies related to AD. Both LXRs are found in microglial cells.(166) Treatment of primary microglia from wild-type mice with Aβ causes an inflammatory response with upregulation of, for example, RANTES, TNFα, IL-1β, COX-2, and inducible NO-synthase (iNOS). In primary mouse microglia, LXR agonist (T0901317 (31)) treatment diminished Aβ-stimulated expression of these pro-inflammatory genes including COX-2 and iNOS, and counteracted NFκB activation.(166,167) Primary microglia from LXR knockout mice displayed diminished ABCA1 expression but similar basal levels of pro-inflammatory genes. Upon Aβ treatment, however, the inflammatory response of LXR knockout microglia was stronger than for wild-type glia.(166) LXR activity, therefore, seems to counteract neuroinflammatory responses to Aβ.
In addition to LXR-mediated anti-inflammatory effects, a potential relevance of LXR in AD is rationalized by the observation that ApoE associates with Aβ plaques and that the ApoE epsilon-4 (ApoE-ϵ4) allele is strongly associated with an increased risk for AD.(168) With levels as high as 5% of extracellular soluble protein, ApoE is highly abundant in the brain.(168) It is secreted mainly by astrocytes and serves for cholesterol transport in the CNS.(168−170) Early in vitro and in vivo studies(171−173) on effects of LXR on ApoE, ABCA1, and Aβ levels have reported conflicting observations. While these studies agree that LXR activation causes ABCA1 upregulation, Fukumoto et al.(171) observed increased secretion of Aβ upon LXR activation, whereas later reports detected decreased cellular Aβ secretion(172) and production(173) upon LXR agonist (T0901317 (31)) treatment.
In transgenic APP23 mice with neuronal expression of a disease-associated APP, a high-fat/high-cholesterol diet was found to exacerbate the disease as observed by a higher Aβ load and impaired spatial learning and memory function. LXR agonist treatment (T0901317 (31)) counteracted these effects of a high-fat/high-cholesterol diet,(174) suggesting an involvement of lipid/cholesterol homeostasis in LXR-mediated effects on Aβ load and cognitive function.
LXR activation with T0901317 (31) in double transgenic APP/PS1 mice expressing human APP with disease-associated mutations and presenilin 1 (PS1) decreased membrane cholesterol levels in the CNS.(175) APP levels were not affected by LXR agonist treatment, but LXR activation reduced β-secretase expression and activity resulting in lower Aβ levels. A connection between membrane cholesterol levels and β-secretase activity was deduced from in vitro experiments in which membrane cholesterol depletion in primary mouse neuronal cells with β-methyl cyclodextrin reduced β-secretase activity. LXR agonist treatment diminished membrane cholesterol levels and β-secretase activity in primary mouse neuronal cells, as well, and this effect was abrogated by ABCA1 inhibition with glyburide. In contrast to these observations, silencing of LXRβ in primary rat neurons expectedly decreased expression of ABCA1 but also lowered cholesterol levels.(176) Concomitantly, HMG-CoA reductase expression and secretion of Aβ were reduced.
Genetic knockout of either LXR subtype in transgenic APP/PS1 mice increased Aβ plaque burden and plaque size with a stronger effect of LXRα knockout.(166) In line with this, treatment of LXR wild-type transgenic APP/PS1 mice with the LXR agonist T0901317 (31) decreased Aβ levels and deposition(167) and reduced microglial activation as well as pro-inflammatory cytokine levels in the CNS. Pharmacological LXR activation furthermore increased the number of cholinergic neurons in the transgenic animals compared to vehicle treatment and improved spatial learning as observed by a maze test. In a related in vivo study using double transgenic APP/PS1 mice, long-term pharmacological LXR activation with T0901317 (31) failed to reduce Aβ plaques but improved memory function in object recognition and object location tests.(177) In a triple transgenic mouse model of AD (3xTgAD, also involving Tau pathology), treatment with the LXR agonist GW3965 (32) increased expression of ABCA1 and ApoE in the CNS.(178) Interestingly, higher ApoE expression upon LXR agonist treatment was mainly found in neurons. Additionally, GW3965 (32) treatment enhanced expression of neural stem cell and proliferation markers. LXR agonist-treated transgenic mice demonstrated significantly improved performance in learning tasks compared to vehicle-treated animals. No effects of LXR agonist treatment on Aβ load were detected, however. These results suggest other mechanisms of LXR activation mediating cognitive improvements in AD. A recent in vitro study(179) on hippocampal neurons suggested that oligomeric Aβ alters expression levels of synaptic proteins and the number of synaptic contacts. Treatment with the LXR agonist GW3965 (32) prevented synaptic changes, increased the expression of neuronal survival genes, decreased caspase activity, and promoted the number of synaptic contacts. The not fully consistent effects of T0901317 (31) and GW3965 (32) in AD-related studies might at least partly arise from different selectivity profiles since T0901317 (31) also modulates RORs.(180)

2.3.4. LXR and Parkinson’s Disease

While the therapeutic potential of LXR modulation in AD has been extensively evaluated, few studies have focused on LXR in PD, but there are observations supporting a role of LXR also in this pathology. In addition to the general anti-neuroinflammatory effects of LXR (2.3.2), the MPTP-induced model of PD has revealed stronger damage of dopaminergic neurons in the substantia nigra and enhanced microglial activation in LXRβ–/– mice compared to wild-type littermates.(181)

2.3.5. LXR and Multiple Sclerosis

As is obvious from the role of LXR in (neuro)inflammatory processes, LXR modulation also holds promise for MS treatment, and several in vitro and in vivo studies support this assumption. In wild-type mice, treatment with the LXR agonist T0901317 (31) promoted expression of the myelin components myelin basic protein and proteolipid protein, while its effects were lost in LXR double knockout animals suggesting LXR involvement in the regulation of these important neural proteins.(164) Similar observations were made in primary cerebellar cultures.(164) LXR signaling was also found to be important to regulate cholesterol homeostasis in OLs which mediate remyelination.(182) T0901317 (31) treatment of OLs enhanced LXR-regulated gene expression and cholesterol efflux.(182) Overall, these results point to a therapeutic potential of LXR in MS but may be compromised by the limited selectivity of LXR agonist T0901317 (31), which is also an inverse ROR agonist.(180) A recent study(183) has provided further evidence for a therapeutic role of LXR in MS and indicates the importance of LXR signaling for a pro-inflammatory to anti-inflammatory switch of microglia in MS lesions which is needed for repair. After demyelination, myelin and cell debris have to be cleared by phagocytosis requiring a pro-inflammatory response before repair mechanisms are initiated in an anti-inflammatory phase.(183) LXR signaling appears to be important in this switch and to provide cholesterol for remyelination.(183) In line with this, levels of the LXR ligand 27-hydroxycholesterol, LXR activity, and LXR-regulated gene expression were induced in human macrophages after myelin phagocytosis in vitro.(184) Autopsies from active human MS lesions confirmed increased LXR signaling and upregulation of ABCA1 and ApoE.(184) Moreover, LXR has been suggested to involve in T cell differentiation to Th17 cells which are key cellular factors of MS pathology.(185) LXR knockout in EAE mice resulted in enhanced Th17 cell differentiation, whereas the LXR activators T0901317 (31) and GW3965 (32) decreased Th17 cell differentiation.(185) In line with this, IL-17 secretion was reduced in wild-type mice upon LXR agonist treatment.(185) In vitro, T0901317 (31) and GW3965 (32) dose-dependently inhibited Th17 cell differentiation which was also observed upon overexpression of either LXRα or LXRβ. T cells from mice with LXRα, LXRβ, or dual knockout revealed the opposite effect.(185)

2.3.6. LXR Ligands

Several potent LXR ligands have been developed as valuable tools and experimental drugs (Scheme 3). The most widely used LXR reference agonists T0901317 (31)(186) and GW3965 (32)(187) activate both LXR subtypes with similar potencies. Activation of brain LXR has been demonstrated for both compounds in animal models, e.g., by increased expression of LXR-regulated genes in the CNS.(171,173,178) T0901317 (31) also is an inverse ROR agonist,(180) which potentially affects outcomes of in vivo studies. AZ12260493 (33) is another agonist of both LXRs, while BMS779788 (34)(188) and WAY252623 (also termed LXR623, 35)(189) exhibit a slight LXRβ preference. Development of LXR ligands with a pronounced subtype selectivity has been hindered by the high similarity of LXRα and LXRβ providing a remaining challenge for future LXR ligand design. The functionally selective LXRβ agonist 36(190) presents as a successful example to overcome the lack of subtype selectivity. It exhibits markedly higher LXRβ activation efficacy (104%) compared to the LXRα subtype (31%) and was developed for the potential treatment of AD-related pathologies based on the hypothesis that LXRβ preference might avoid hepatic side effects but exhibit full therapeutic efficacy in the brain. 36 was brain-penetrant in mice and rhesus monkeys and increased CNS levels of ABCA1 and ApoE. As hypothesized, no adverse effects on liver triglycerides were observed upon treatment with 36 in either species. In Tg2576 mice overproducing Aβ peptides, 36 caused a reduction of Aβ levels in the brain and improved locomotor activity. In rhesus monkeys, 36 induced a 3-fold increase in brain ApoE levels, while a related compound with high P-gp efflux ratio did not alter ApoE indicating that the effect of 36 was mediated by brain LXR activation. 36, therefore, appears as very promising tool to study LXRβ activation in neurodegeneration with reduced adverse effects of hepatic LXRα agonism.

Scheme 3

Scheme 3. Selected LXR Ligands

2.3.7. Conclusion

As a key regulator of cholesterol homeostasis and anti-inflammatory transcription factor, LXR has attracted attention as a potential target in AD and MS (Table 3). Anti-inflammatory effects in microglia have been demonstrated for LXR activation, and a role in AD is rationalized by the LXR-dependent regulation of ApoE expression, although some observations on LXR in AD models are controversial. LXR agonist tools with sufficient BBB penetration are available, and several studies support the potential of pharmacological LXR activation in AD and MS treatment. Some promising observations, especially regarding anti-inflammatory effects, are compromised by the use of the LXR agonist 31 as tool, which also has considerable potency as an inverse ROR agonist. Among the two LXR isoforms, LXRβ activation has shown greater therapeutic potential in neurodegeneration and less adverse hepatic effects, but fully subtype selective LXR agonists to exploit this potential are lacking, and novel LXR modulators are needed. The functionally selective and brain penetrant LXRβ agonist 36 is a promising example of a next-generation tool to capture the effects of LXRβ activation in the CNS.
Table 3. Summarized Observations on LXRs in Neurodegeneration
LXRα (= NR1H3; also known as RLD-1) and LXRβ (= NR1H2; also known as UNR, NER, and RIP15)
LXRs in ADLXR activation ameliorated and LXR knockout enhanced the inflammatory response of microglia to Aβ.(166,167)
LXR knockout in transgenic AD mice increased Aβ plaque burden and plaque size.(166)
Observations regarding effects of LXR activation on Aβ levels are inconsistent.(167,171−173)
Long-term LXR agonist treatment improved cognitive function in transgenic AD mice.(177)
LXRs in PDLXRβ knockout in MPTP-induced PD enhanced microglial activation and dopaminergic neuron damage.(181)
LXRs in MSLXR activation promoted expression of myelin components (myelin basic protein, proteolipid protein).(164)
LXR signaling was found to be important in regulating cholesterol homeostasis in (myelinating) OLs(182) and to provide cholesterol for remyelination.(183)
In EAE, LXR knockout enhanced and LXR agonist treatment decreased Th17 cell differentiation.(185)

2.4. Vitamin D Receptor (VDR)

2.4.1. Overview

The vitamin D receptor (VDR, NR1I1) is a cellular sensor for vitamin D with 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) as the main endogenous ligand.(150) It binds the DR3 response element as a heterodimer with RXR. VDR is essentially involved in the regulation of vitamin D and calcium homeostasis by controlling expression of crucial enzymes for vitamin D biosynthesis and degradation.(150)

2.4.2. VDR in Neurodegenerative Diseases

The importance of calcium homeostasis in the neuronal system for Ca2+ signaling provides a link between VDR, neuronal function, and neurodegeneration.(191) Additionally, VDR has been ascribed a cell-protective role against toxic metabolites(150,192,193) that might contribute to neuroprotective effects. In the brain, VDR is expressed in neurons and glial cells,(194) and VDR knockout in mice caused motor impairment without affecting cognitive function.(195)
In recent years, a number of reports on VDR-mediated beneficial effects in neurodegenerative diseases have accumulated. Most notably, VDR genetic polymorphisms in humans were correlated with AD or PD, among which one single-nucleotide polymorphism (SNP) showed correlation with both diseases,(196−198) suggesting VDR as a potential susceptibility gene. Genetic polymorphisms of VDR were also found in MS patients.(199) Evidence for the importance of sufficient vitamin D levels in AD, PD, and MS also results from epidemiological and clinical studies.(199−204) In PD, vitamin D supplementation appears beneficial,(200,202) and a correlation between vitamin D deficiency and AD is proposed(201) as epidemiological studies have revealed high prevalence of hypovitaminosis D(201) in AD patient populations. Moreover, prospective studies involving samples of up to 7 million individuals found a correlation between high vitamin D levels and decreased MS risk.(203,205) Altered expression of AD-associated VDR-regulated genes was detected in the brains of mice with hypovitaminosis D,(206) suggesting that low vitamin D levels affect gene expression in the brain.
In vitro, a protective potential of VDR signaling in neuronal cell populations including astrocytes as brain immune cells has been demonstrated in several studies.(207−210) Moreover, it has been proposed that Aβ formed in AD suppresses VDR expression, while administration of vitamin D counteracted this effect.(211) Vitamin D was also found to inhibit LPS-induced astrocyte activation in vitro and in rats,(210) suggesting an anti-neuroinflammatory potential. In line with this, in vivo studies have reported therapeutic effects of vitamin D and analogues in EAE.(212) In the context of PD, diminished VDR expression was detected in the 6-OHDA-induced and the preformed fibril (PFF) injection rodent models of PD.(213) The reduced VDR activity resulted in decreased P-gp levels, which is thought to be important for clearance of intracerebral α-synuclein load in PD.(213) Treatment with 1,25(OH)2D3 counteracted these effects and restored VDR and P-gp activity.(213)

2.4.3. VDR Ligands

Despite promising preliminary data, the potential of VDR as a therapeutic target for neurodegenerative diseases remains to be validated. Several potent (up to sub-nanomolar EC50 and Kd values) and selective VDR modulators (3741, Scheme 4) including vitamin D analogues and nonsteroidal compounds are available.(214) They can serve for further functional in vivo studies in the context of neurodegeneration. Adverse effects on calcium homeostasis may, of course, limit a long-term therapeutic VDR modulation in neurodegenerative diseases, but extensive efforts in medicinal chemistry(214) have provided potent VDR modulators with low calcemic effects in vivo (e.g., 39) that might overcome this obstacle.

Scheme 4

Scheme 4. Potent and Selective VDR Ligands (Agonists 3740; Antagonist 41) from the Literature(214−217) as Potential Tools for Functional Studies in Neurodegeneration

2.4.4. Conclusion

Disease-associated SNPs of VDR and the correlation between vitamin D levels and incidence of neurodegenerative diseases provide the strongest evidence for a potential involvement of VDR in neurodegeneration (summarized in Table 4), and motor impairment observed in VDR knockout animals further supports this assumption. However, mechanistic understanding of VDR involvement in neurodegenerative diseases is incomplete, and studies on effects of pharmacological VDR modulation in this context are limited despite the availability of multiple potent and selective VDR modulators. Although involvement of brain VDR in the observed effects, for example, regarding anti-neuroinflammatory activity has been demonstrated, contributions of peripheral VDR activation remain to be evaluated, and adverse effects of systemic VDR activation must be considered.
Table 4. Summarized Observations on VDR in Neurodegeneration
VDR (= NR1I1)
VDR in ADGenetic polymorphisms of VDR were correlated with AD.(196)
High prevalence of hypovitaminosis D in AD patients.(201)
Low vitamin D levels altered expression of AD-associated genes in mice.(206)
VDR in PDGenetic polymorphisms of VDR were correlated with PD.(197,198)
Beneficial effects of vitamin D supplementation.(200,202)
VDR expression was diminished in 6-OHDA-induced PD.(213)
VDR knockout in mice caused motor impairment without affecting cognitive function.(195)
VDR in MSGenetic polymorphisms of VDR were correlated with MS.(199)
High vitamin D levels correlated with lower MS risk.(203,205)
VDR activation inhibited LPS-induced astrocyte activation in vitro and in rats.(210)
VDR activation ameliorated EAE.(212)

2.5. Retinoid X Receptors (RXR)

2.5.1. Overview

RXR belongs to the second subfamily of nuclear receptors and has the typical NR structure. It exists in three subtypes which are encoded by independent genes(218) but still exhibit very high structural similarity, especially in the LBD. The amino acids, which are responsible for the formation of the ligand binding site, are identical in all three subtypes.(219−221) A key feature of RXR is that it acts as a universal heterodimer partner for many other NRs.(21) These heterodimers are distinguished between permissive (e.g., PPAR/RXR, FXR/RXR and LXR/RXR) and nonpermissive heterodimers (e.g., RAR/RXR)(21) (Figure 2). Nonpermissive heterodimers can only be activated by ligands of the heterodimer partner and not by an RXR agonist alone.(21) In contrast, permissive heterodimers can be activated by ligands of RXR and by ligands of the heterodimer partner, and are synergistically activated in the presence of ligands for both partners.(21)

Figure 2

Figure 2. Role of RXR in NR heterodimers. Permissive heterodimers respond to RXR ligands and to ligands of the heterodimer partner. The presence of ligands for both partners causes synergistic activation. Nonpermissive heterodimers can only be activated by ligands of the heterodimer partner.(21)

Owing to this important role in the NR network, at least one subtype of RXR is expressed in every cell that has a nucleus,(218,222) but the subtype distribution differs. In mice, RXRα was found distributed over the whole body but with particularly high expression in the liver, spleen, epidermis, and kidney.(218,223) For RXRß, no explicit expression pattern could be observed, resulting in the assumption that this subtype is almost ubiquitous.(218,223) Regarding neurodegenerative diseases, it is important to mention that, in contrast to the other two subtypes, higher CNS localization was observed for RXRγ. Additionally, this subtype is found in heart muscles, adrenal glands, and muscle cells.(218,223) Within the CNS, there is no distinct distribution. RXRγ is expressed in the striatum, parts of the amygdala, the spinal cord, and in the hypothalamus.(224,225) A particularly high expression was found in basal ganglia, and an association with motor function and addiction has been suggested.(226) Especially noteworthy is the high expression of RXRγ in glial cells,(226) as these cells are involved in pathophysiological processes in neurodegenerative diseases.(227,228)
Because of its crucial involvement in numerous (patho-)physiological processes as a universal NR heterodimer partner, the pharmacological potential of RXR may be very high. In addition to the established role of RXR activation in the field of cancer therapy,(222) the role of RXR in neurodegenerative diseases has been intensively studied in recent years. Therein, RXR involves in neuroprotective, neuroinflammatory, and regenerative processes regulated by its heterodimers.(229) Especially for the treatment of AD, MS, and PD, RXR is evolving as an attractive target.

2.5.2. RXR in Alzheimer’s Disease

One of the major risk factors for the development of AD is ApoE, especially the ApoE-ϵ4 variant.(230−234) Together with the ABCA1, ApoE regulates the lipid and cholesterol transport in the CNS.(235) ABCA1 mediates the cellular efflux of phospholipids and cholesterol toward ApoE.(236) It has been proposed that ApoE inadequately equipped with lipids and cholesterol affects the accumulation and transport of Aβ.(235,237,238) Both the ApoE and the ABCA1 genes are under transcriptional control of the PPARγ/RXR- and LXR/RXR-heterodimers.(230) For this reason, an RXR agonist could exhibit a dual effect through the simultaneous activation of both heterodimers, since both heterodimers are permissive.(23)
Therapeutic effects of RXR agonists have been observed in common preclinical models of AD. In APP/PS1 mice, acute treatment with bexarotene (42) caused a removal of diffuse and compact Aß plaques in the cortex and hippocampus, elevated levels of ApoE, ABCA1, and ABCG1, reduced soluble and insoluble Aβ levels, counteracted cognitive and behavioral deficits and restored cognition and memory.(239) The bexarotene (42)-treated APP/PS1 mice also showed an improved hippocampal function, and in total, the Aβ plaques were reduced by 75%.(239) This acute and chronic efficacy of RXR activation with bexarotene (42) in AD in both early and late stages presents as a very attractive and promising therapeutic strategy. However, four independent groups, despite also observing therapeutic effects, failed to reproduce these findings thoroughly.(240−243)
The effects of bexarotene (42) in AD have also been investigated in two small clinical studies. A phase 1 trial with 12 patients receiving either 450 mg/day bexarotene (42) or placebo reported that only a very small proportion of bexarotene (42) enters the CNS. Bexarotene (42) treatment only slightly elevated ApoE levels in CSF and had no effect on the synthesis, clearance, or total levels of Aβ in CSF.(244) In a small, double-blind, placebo-controlled phase 2 trial, 20 patients with AD were randomized to receive 300 mg/day of bexarotene (42) or placebo for 4 weeks.(245) No difference regarding composite or regional Aβ burden was observed between bexarotene (42) and placebo when all patients were included in the analysis.(245) However, ApoE-ϵ4 noncarriers showed reduced Aβ burden in all measured cortical regions after bexarotene (42) treatment compared to placebo.(245) In addition, an observed correlation between reduced cortical Aβ and an increasing serum level of Aβ1–42 potentially indicates an excretion of soluble Aβ forms from brain to blood.(245) This short-term trial was not powered to detect cognitive changes, however.(245)

2.5.3. RXR in Parkinson’s Disease

Similar to AD, involvement of RXR in PD is connected with permissive RXR heterodimer formation. In the case of PD, the permissive RXR/Nurr1 heterodimer is most relevant due to the key role of Nurr1 in PD (see section 2.7.2).(2,246)

2.5.4. RXR in Multiple Sclerosis

An involvement of RXR in MS is evident from the fact that its expression is elevated upon CNS damage.(247) An increased expression of RXRγ in OPCs, which develop into adult OLs and are responsible for the formation of the myelin layer, has been detected in MS lesions.(227) OLs can repair damage to myelin sheaths caused by MS-associated autoimmune inflammation to a certain extent and thus may have regenerative potential.(227) The increased RXRγ expression was observed both in rats with toxin-induced central demyelination and post mortem in human tissue samples.(227) Moreover, RXRγ knockout mice displayed significantly less differentiated OLs in lesions after toxin-induced demyelination compared to wild-type animals.(227)
A second possible mechanism of RXR involvement in MS(248) refers to the fact that myelin fragments resulting from demyelization inhibit OPC differentiation.(249,250) Removal of these fragments represents an important step in the regeneration of CNS damage. Macrophage-specific RXRα knockout mice exhibited reduced myelin phagocytosis capacity after induced demyelination and delayed OPC differentiation,(248) suggesting involvement of RXR in this process together with its heterodimer partners PPAR and LXR (see sections 2.1 and 2.3). Moreover, an interesting reversal of functional defects in myelin phagocytosis by MS monocytes upon bexarotene (42) treatment was observed in patient-derived monocyte samples.(248)
The effect of RXR activation in MS was examined in several preclinical models. In vitro, 9-cis RA (43) exhibited anti-inflammatory effects on microglia and astrocytes by inhibiting the production of pro-inflammatory cytokines, such as TNFα and IL-1ß.(251) RXR activation hence counteracted neuroinflammation and might intervene in the acute phase of the disease. Furthermore, 9-cis RA (43) promoted the differentiation of OPCs ex vivo and enhanced myelin basic protein production.(227) In focal toxin-induced demyelination in aged rats, 9-cis RA (43) enhanced expression of myelin basic protein mRNA in lesions and accelerated remyelination.(227) In addition to 9-cis RA (43) and bexarotene (42), the second-generation rexinoid IRX4204 (90, see section 2.7.2.6) has been studied in several preclinical models of MS. It alleviated the symptoms of EAE in mice and supported the differentiation of OPCs from mouse brains to OLs.(252) In focal toxin (ethidium bromide) induced demyelination in rats (one-year-old), IRX4204 (90) treatment caused an increase in CNS remyelination,(252) and in a mouse model of nonimmune-mediated demyelination, IRX4204 (90) exhibited neuroprotective activity by directly affecting demyelinated axons.(252)

2.5.5. RXR Ligands

As outlined above, RXR has a central role in the network of NRs as a heterodimer partner. From this unique characteristic, a potential involvement of RXR in multiple regulatory systems can be inferred since the majority of RXR heterodimers is permissive, meaning that they can be activated by RXR agonists.(253) In addition, ligand-dependent allosteric modulation between the heterodimer partners is discussed.(26) The resulting therapeutic potential of RXR modulation in multiple indications has stimulated considerable efforts in RXR ligand development. In addition to the high similarity of the three RXR isoform LBDs,(221) the RXR ligand binding sites are very lipophilic and provide little potential for polar ligand–protein interactions.(221,222) Consequently, the majority of RXR ligands are exceptionally lipophilic.
Very early on, metabolites of vitamin A were suspected as natural RXR ligands, and based on this, 9-cis RA (43, Scheme 5) was identified as a high-affinity ligand.(107,254) Reported EC50 values for 9-cis RA (43) vary depending on the test system between 1.7 and 200 nM for all RXR subtypes.(222,254−258) Because of its low endogenous levels, the physiological relevance of 9-cis RA (43) is controversially discussed, however. Exogenous 9-cis RA (43) has therapeutic relevance (as alitretinoin) to treat chronic hand eczema and skin lesions in connection with Kaposi’s sarcoma(259,260) and is studied for the treatment of atopic dermatitis and psoriasis.(261) 9-Cis-13,14-dihydroretinoic acid (44), another metabolite of vitamin A, activates RXR as well and was detected in mice at relevant levels.(262,263) In addition, several fatty acids were discovered as potential endogenous RXR ligands including docosahexaenoic acid (DHA, 45), oleic acid (46), palmitic acid (47), and stearic acid.(221,222,256,264,265) The potency of these fatty acids on RXR is limited (micromolar range), however, and despite considerable concentrations found in plasma and even the brain, a physiological relevance remains to be demonstrated.

Scheme 5

Scheme 5. Selected RXR Ligands
The first potent synthetic RXR agonists were based on the structure of 9-cis RA (43), which conforms well to the L-shaped ligand binding pocket of RXR. The most prominent synthetic RXR agonist is bexarotene (42) is the only synthetic RXR ligandthat has received drug approval to date. It is used as a second-line therapy in the treatment of cutaneous T cell lymphoma.(222,266,267) Bexarotene (42) is a pan-RXR agonist with similar potency on all three subtypes (EC50: RXRα: 33 nM, RXRβ: 24 nM, RXRγ: 25 nM)(268) and comprises nonfavorable physicochemical properties(117) with exceptionally high lipophilicity (logP 6.9), low solubility, and poor pharmacokinetics.(117,269,270) In addition, bexarotene (42) is associated with risks/adverse effects(271) such as severe disturbances in lipid homeostasis (elevated triglyceride and cholesterol levels), leukopenia, hypothyroidism, and an increased risk of acute pancreatitis. From bexarotene (42), several other rexinoids were developed such as SR11237 (48, EC50: RXRα: 29 nM, RXRβ: 98 nM, RXRγ: 232 nM),(272) LG100268 (49, EC50: 3–4 nM),(273) PA024 (50, EC50: RXRα: 3 nM, RXRβ: 24 nM, RXRγ: 8 nM),(272) NEt-3IP (51, EC50: RXRα: 32 nM, RXRβ: 36 nM, RXRγ: 376 nM),(274) and NEt-3IB (52, EC50: RXRα: 0.58 nM, RXRβ: 23 nM, RXRγ: 3 nM).(274) Derived from the unselective PPAR agonist Wy14-643 (14),(275) the RXR agonist 53(117) has been developed as a potent next-generation RXR ligand with strong selectivity, superior physicochemical properties, and improved pharmacokinetics. RXR antagonists were obtained from rexinoid scaffolds by introduction of bulky side chains.(276,277) Representative RXR antagonists useful as tool compounds are HX531 (54, IC50: RXRα: 1 μM), LG100754 (55, IC50: RXRα: 16 nM), and UVI3003 (56, IC50: RXRα: 0.24 μM).(276)
Progress has recently been made in subtype selective targeting of RXR. The natural product valerenic acid (57) was discovered as an RXRβ agonist with functional preference. In addition to a lower EC50 value for RXRβ activation (EC50: RXRα: 27 μM, RXRβ: 5.2 μM, RXRγ: 43 μM) valerenic acid (57) exhibits remarkably higher efficacy on the RXRβ subtype (fold activation: RXRα: 9-fold, RXRβ: 69-fold, RXRγ: 4-fold).(278) Moreover, computational de novo design(279) has yielded biphenyl-based RXR modulators, which could be tuned in their subtype-preference profile as exemplified by the RXRβ preferential compound 58.(280) Together, these results demonstrate that RXR subtype selectivity can be achieved despite their high LBD similarity.(221)

2.5.6. Conclusion

Because of its ability to act as a universal heterodimer partner for multiple other NRs, RXR is involved in various aspects of neurodegenerative diseases (summarized in Table 5) and has been intensively studied for this role in recent years. Despite some controversial reports, therapeutic effects of pharmacological RXR activation in many preclinical models support a promising therapeutic potential of RXR especially in AD and MS. Most remarkably, pharmacological RXR activation reduced Aβ plaques in cortex and hippocampus of AD mice, promoted remyelination in mouse models of MS, and reversed functional defects of MS monocytes in myelin phagocytosis. However, available RXR agonists such as bexarotene (42), 9-cis RA (43), or IRX4204 (90), though exhibiting remarkable potency, have several limitations. BBB penetration was found to be very low for bexarotene (42) and is likely poor for the other structurally related rexinoids due to their common carboxylic acid group. The low CNS bioavailability of the RXR agonist tools used in the preclinical studies might raise the question of whether the attractive effects were actually mediated by RXR activation in the brain. However, several studies have included knockout or antagonist control experiments, suggesting that RXR in the CNS is at least in part involved in the therapeutic activities. Moreover, the involvement of the universal heterodimer partner RXR in multiple nuclear receptor signaling systems and the associated adverse effects that were, for example, observed with bexarotene (42), demand the development of subtype selective RXR modulators. The recent discovery of valerenic acid (57) as a selective RXRβ agonist(278) demonstrates that this selectivity can be achieved despite remarkable similarity of the three RXR isoforms.(221) Hence, a lot of further research is needed to enable subtype selective RXR activation in the brain and to capture the full potential of RXR modulation in neurodegenerative diseases.
Table 5. Summarized Observations on RXR in Neurodegeneration
RXRα (= NR2B1), RXRβ (= NR2B2; also known as H-2RIIBP and RCoR-1) and RXRγ (= NR2B3)
RXR in ADIn APP/PS1 mice, bexarotene (42) treatment (3, 7, or 14 days) reduced Aβ levels and caused removal of Aβ plaques, elevated ApoE, ABCA1, and ABCG1 levels, restored cognition and memory function, and improved hippocampal function.(239)
In human patients, bexarotene (42) treatment slightly elevated ApoE levels in CSF but had no effect on synthesis, clearance, or total levels of Aβ. ApoE-ϵ4 noncarriers showed reduced Aβ burden.(244,245)
RXR in MSRXRγ-knockout mice had less differentiated OLs in lesions after toxin-induced demyelination.(227)
RXRα-knockout mice exhibited reduced myelin phagocytosis after demyelination and delayed OPC differentiation.(248)
Bexarotene (42) reversed functional defects of MS patient monocytes in myelin phagocytosis.(248)
9-cis RA (43) exhibited anti-inflammatory effects on microglia and astrocytes by inhibiting the production of pro-inflammatory cytokines, such as TNFα and IL-1ß.(251)
9-cis RA (43) and IRX4204 (90) caused CNS remyelination in young and aged rats after toxin-induced demyelination.(227,252)
IRX4204 (90) alleviated symptoms of EAE in mice and promoted differentiation of OPC.(252)
RXR in PDSee permissive RXR/Nurr1-heterodimer.

2.6. Tailless Homologue (TLX, NR2E1)

2.6.1. Overview

The orphan NR TLX (NR2E1) is one of the least studied and most elusive nuclear receptors. It is considered a master regulator of neural stem cell (NSC) maintenance(281) and is evolutionarily conserved in vertebrates and invertebrates. TLX was found to exhibit an essential role in embryonal brain development, and high TLX expression in adults was detected exclusively in quiescent and rapidly dividing NSCs in neurogenic regions as well as in retinal progenitor cells.(282−285)
Mechanistically, TLX appears to differ from other nuclear receptors in a number of aspects. In line with its role in maintaining NSCs in a proliferating state and the underlying suppression of pten and p21, TLX was found to act mostly as a negative regulator of gene expression. It binds to the NR response element sequence AAGTCA as a monomer with high affinity(286) and according to current knowledge differs also in its corepressor recruitment profile from most other NRs as it strongly binds atrophin, lysine-specific histone demethylase 1A (LSD-1), and histone deacetylases to inhibit gene expression.(286−291) Structurally, TLX comprises the typical architecture of NRs despite a shorter LBD that lacks the first two of 12 helices which are present in most NRs.(286) Early modeling approaches suggested that TLX may possess a ligand binding pocket within the LBD,(286,292) but evidence from a cocrystal structure supporting this assumption is lacking. A TLX apo structure revealed the terminal α helix H12 of TLX bound at the canonical coactivator binding site of nuclear receptors indicating an autorepression.(293) This autorepressed state resembles other NRs with repressor activity such as the TLX-related photoreceptor-specific nuclear receptor (PNR, NR2E3)(294) and the dosage-sensitive sex-reversal adrenal hypoplasia congenital critical region on the X chromosome gene 1 (Dax-1, NR0B1).(295) The putative ligand binding site of TLX is mostly blocked by bulky hydrophobic residues in the apo structure.(291,293) Molecular dynamics and subsequent mutagenesis studies have suggested a potential binding site (for rexinoids) inside the TLX LBD close to the interface of helices H3 and H11.(291) This site has a higher solvent exposure than the ligand binding pockets of common NRs and is not present in the apo structure but requires conformational changes of H11 or H3 depending on the ligand type.(291,293)

2.6.2. TLX in Neurodegeneration

Despite limited knowledge on TLX and the lack of TLX modulator tools for functional studies, there is preliminary evidence for a great potential of TLX in neurodegenerative diseases. In the brain, TLX regulates the maintenance of NSC populations and neurogenesis.(281,290) It governs behavior and activation of NSCs(281) through directly controlling the expression of the tumor suppressor pten and the cyclin-dependent kinase inhibitor p21, thereby enabling re-entry in the cell cycle.(281,284,286) Accordingly, the putative TLX activator oleic acid (46) was recently shown to induce NSC mitosis and neurogenesis in mice.(296) Thus, maintaining NSCs in the brain in a proliferating, self-renewing state and preventing their differentiation appear to be key roles of TLX.(281,282,297−299) NSCs are found in at least two main regions of the adult (human) brain, the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle, from where NSCs initiate the formation of new neurons.(281,282,300) TLX appears to be a key regulator of this process by maintaining a balance between proliferating NSCs and differentiated neurons.(281,282,300) The absence of TLX, accordingly, caused an entire loss of neurogenesis.(301) A number of knockout studies in rodents have revealed promising links of TLX to neurological and neurodegenerative diseases. TLX knockout led to limbic defects, hyperactivity, and violent behavior in adult mice.(281,302,303) Concomitantly, active neurogenic regions in the brains of these mice showed severe deficits.(281,304) NSCs from TLX knockout mice were unable to proliferate and self-renew, while an ectopic expression of TLX efficiently rescued this ability.(281,282) A brain-specific TLX overexpression in mice led to improved learning capacity and memory function.(305)
These observations from in vitro and in vivo studies together draw a picture of TLX as a crucially important regulator of neuronal health and neuro-regeneration, and demonstrate an involvement of the orphan NR in spatial learning and cognitive functions during adolescence and adulthood.(281,306−308) Moreover, TLX mutations in humans are linked to microcephaly and mental diseases such as bipolar disorders and schizophrenia.(281,309) A recent study observed a correlation between schizophrenia risk and certain TLX haplotypes that were predicted to affect the expression rate of TLX,(310) ascribing the orphan NR also a key role in mental health. Overall, compelling evidence points to a great therapeutic potential of targeting TLX in neurodegeneration and neurological diseases.
In addition to its involvement in neuronal and retinal function, TLX has been associated with glioblastoma development, the most common and a highly aggressive brain tumor.(311−313) The orphan NR was found overexpressed in tumor stem cells of glioblastoma,(312) while TLX knockdown decreased tumor progression and enhanced survival in a xenograft tumor model in mice.(314) TLX modulators, therefore, might hold strong potential in this context as well. However, there is no evidence that ectopic TLX overexpression in animal models promotes cancer development,(291) which is an important aspect for pharmacological targeting of TLX in neurodegeneration.

2.6.3. TLX Ligands and Modulators

A number of studies have demonstrated that TLX activity can be modulated by small molecule ligands, and a few TLX modulators with mostly weak potency (micromolar range) have been described(286,291,292,315) (Scheme 6). Benod et al.(292) were the first to report small molecule modulators of TLX from a medium-throughput screening campaign. By differential scanning fluorimetry with the recombinant TLX LBD protein, they identified 190 primary hits from a library of 20 000 compounds. Three compounds (famprofazone, ccrp1 (59); ccrp2 (60); dydrogesterone, ccrp3 (61)) showed activity on TLX in an orthogonal cellular reporter gene assay. In another study,(315) the activity of famprofazone (59) and ccrp2 (60) (ccrp3 (61) was not tested) could not be reproduced, however. Dueva et al.(315) applied a computational approach to TLX ligand discovery and reported 6264 as TLX modulators in a cellular setting. Orthogonal validation of these compounds as TLX ligands is pending, however, and they comprise PAINS suspect elements. Retinoids (ligands of the nuclear retinoic acid receptors, RARs) have recently been proposed to act as TLX modulators, too. In vitro, certain natural (all-trans retinal, ATRAL (65)) and synthetic (BMS453 (66); CD1530 (67)) compounds showed TLX activation or inverse agonism with potencies ranging approximately between 0.2 μM and 2 μM.(291) Retinoid efficacy in TLX activation (∼5-fold, BMS453 (66)) and repression (∼4-fold, ATRAL (65)) was limited, however. NMR experiments were employed to orthogonally validate a direct interaction between TLX and the retinoids, which revealed chemical shift perturbations and line broadening.(291) Another recent study(296) has discovered oleic acid (46) as a putative endogenous TLX ligand that is capable of switching TLX activity from transcriptional repression to cell cycle activation and was shown to be present in human NSCs.

Scheme 6

Scheme 6. TLX Ligands Reported in the Literature(291,292,315)

2.6.4. Conclusion

Despite a very limited understanding of TLX, the essential regulator of NSC homeostasis holds remarkable promise in neurodegenerative diseases (summarized in Table 6). However, owing to the lack of TLX modulators as tools, functional understanding of TLX is incomplete, and insights in its (patho-)physiological role stem only from knockout experiments. Current evidence of TLX mutations disrupting neurogenesis and knockout causing abnormal brain development and behavioral deficits points to a high potential of targeting TLX for regenerative approaches in neurodegeneration. Therein, the exclusive expression of TLX in certain brain regions may suggest few adverse effects of TLX modulation since no other tissues would be affected. However, the known TLX ligand space is very limited and somewhat controversial. Biochemical and biophysical characterization of most putative TLX modulators is not comprehensive. Broad reproduction of their activities in various settings and orthogonal validation is pending. Despite preliminary data, binding sites and the molecular mode-of-action remain elusive for TLX. With their limited potency, efficacy, and selectivity, and their unclear modes of action, the available TLX ligands are insufficient for pharmacological evaluation and validation of the orphan NR. More potent, selective, and broadly profiled TLX agonists and inverse agonists are required as pharmacological tools for target validation. The development of potent TLX ligands as highly profiled tools for functional studies on TLX is imperative.
Table 6. Summarized Observations on TLX in Neurodegeneration
TLX (= NR2E1; also known as TLL and XTLL)
TLX in neurodegenerationTLX mutations in human were associated with microcephaly and mental diseases.(281,309)
TLX regulates the maintenance of NSCs and neurogenesis.(281,290)
TLX maintains a balance between proliferating NSCs and differentiated neurons.(281,282,300)
TLX knockout led to defects in neurogenesis,(281,304) limbic defects, hyperactivity, and violent behavior in adult mice.(281,302,303)
Brain-specific TLX overexpression improved learning capacity and memory function.(305)

2.7. NR4A Receptors

2.7.1. Nur77 (NR4A1)

2.7.1.1. Overview
As the first member of the NR4A subfamily of NRs, Nur77 was originally identified as nerve growth factor-induced clone B (NGFI-B)(316) and is an orphan nuclear receptor since no endogenous ligands are known so far. Nur77 was thought to be a ligand-independent transcription factor due to its closed and tightly packed conformation of the LBD in which the canonical ligand binding pocket is occupied by bulky hydrophobic amino acids that are conserved among the three NR4A subfamily members.(317) The resulting autoactivated conformation (Figure 3c) renders Nur77 (and the related NR4A receptors Nurr1 and NOR-1) as a constitutively active transcriptional inducer with high transcriptional activity in the absence of a ligand. Nur77 can act in three forms, as a monomer on NGFI-B response elements (NBRE), as a homodimer on Nur response elements (NurRE), which were first detected in the promoter region of the proopiomelanocortin (POMC)(318) gene, or as a heterodimer with an RXR on DR5 response elements.(319−321) Nur77 is widely expressed in several tissues including the pituitary gland, adrenal gland, thyroid, liver, testis, ovary, thymus, muscle, lung, and prostate(29) but also in the nervous system with the highest levels in the cerebral cortex and hippocampus.(322) In contrast to Nurr1, it is highly expressed in target areas of dopaminergic neurons such as the striatum, nucleus accumbens, and prefrontal cortex. Interestingly, Nur77 mRNA was not found in the prenatal CNS but only in the adult brain.(323) The functions of Nur77 are manifold and appear to be tissue specific. In metabolic diseases like diabetes, it seems to participate in the regulation of blood glucose levels since genetic deletion of Nur77 in mice increased insulin resistance.(324,325) Also several inflammatory conditions such as asthma,(326) atherosclerosis,(327,328) arthritis,(329) and sepsis(330) are linked to Nur77 activity. Additionally, Nur77 is overexpressed in multiple solid tumors and plays a pro-oncogenic role in cancer (reviewed in Beard et al.(331)). Moreover, Nur77 was shown to induce apoptosis by targeting mitochondria, whereby it translocates from the nucleus to the cytoplasm in an RXRα regulated fashion,(332,333) suggesting that Nur77 also exhibits activities via non-transcriptional mechanisms.

Figure 3

Figure 3. Comparison of the crystal structures of “classical” nuclear receptors (RXRα) and NR4A receptors (Nur77). (a) The apo structure of the RXRα LBD (pdb 3R29) in complex with the corepressor peptide SMRT (magenta) reveals the NR in its inactive state in which the C-terminal α-helix (H12, colored red) comprises the AF-2 in an unordered conformation. (b) The ligand-activated state of RXRα (pdb 3OAP) shows the NR cocrystallized with its endogenous ligand 9-cis RA (43) and the coactivator peptide TIF2 (neon green) with H12 in its active conformation. (c) The apo structure of the Nur77 LBD (pdb 3V3E) reveals the NR in an autoactivated state with H12 coordinated to the LBD core without a bound ligand. (d) Ligand-activated cocrystal structure (pdb 6KZ5) of the Nur77 LBD in complex with agonist Csn-B (68, purple) superimposed with ligand binding pockets and their respective ligands from other Nur77 cocrystal structures revealing other binding sites with high solvent exposure. Csn-B (68, purple) is bound at the dimeric interface, THPN (71, teal, pdb 4JGV) is protruding toward a sub-pocket between H5 and H7, and TMPA (69, blue and orange, pdb 3V3Q) is bound to two different sites. Site A (orange) is located at the interaction site of H12, which resembles the binding pockets identified for covalently bound Nurr1 ligands DHI (83) and PGA1 (80), while site B (blue) constitutes a cavity on the surface close to helices 1, 5, and 8. Alignment and superposition of the structures were performed in MOE 2020.09.

2.7.1.2. Nur77 in Parkinson’s Disease
Growing evidence, mainly from PD models, ascribes Nur77 a role in in neurodegenerative diseases. Although Nur77 knockout mice(334) and rats(335) exhibited only a mild phenotype, they tended to have higher basal locomotor activity. In line with this, a SNP in the Nur77 gene was found to be strongly associated with tardive dyskinesias in a cohort of schizophrenic patients.(336) Several studies further investigated the role of Nur77 in drug-induced dyskinesias and PD models with somewhat controversial results. Still, all studies demonstrate involvement of Nur77 in aberrant dopamine-related behavior.
Full Nur77 knockout in mice displayed beneficial effects on dopamine neuron function.(334) Moreover, the regulation of the neuropeptides enkephalin and neurotensin was shown to be Nur77 dependent in the context of dopamine denervation in 6-ODHA-lesioned mice;(337) however, they remain to be validated as direct Nur77 target genes.(337,338) In two MPTP animal models, Nur77 was downregulated,(339,340) and Nur77 knockout resulted in a sensitization to dopaminergic cell death following MPTP treatment.(340) In drug-induced dyskinesia, induction of Nur77 by administration of RXR agonist DHA (45) following levodopa treatment ameliorated symptoms.(339) The latter was proven with DHA (45) administration in Nur77 knockout mice,(341) which failed to counteract haloperidol-induced dyskinesia pointing toward a potential involvement of the Nur77-RXR heterodimer.
The findings of Rouillard et al.(335) and Wei et al.(342) are hence controversial: Although Nur77 expression is almost negligible in substantia nigra and the ventral tegmental area, rapid upregulation of Nur77 in substantia nigra and midbrain was observed in a 6-OHDA-induced rat PD model with concomitant downregulation of Nurr1 and TH in midbrain.(335) Moreover, Nur77 deficiency decreased dopaminergic neuronal loss in two different rodent PD models.(335) Accordingly, Nur77 protein expression was rapidly upregulated upon 6-OHDA treatment in vitro, and Nurr1 protein expression decreased over time, supporting a contradirectional coupling of these two receptors in the context of neurodegeneration.(342,343) The NMDA receptor antagonist memantine and lentiviral Nur77 knockdown reversed these effects, prevented neurodegeneration by inhibiting Nur77 translocation to the cytosol, and promoted neuroprotection via post-translational modifications of Nurr1.(342)
Contributions of Nur77 to neuroinflammation in the context of PD are more consistent. In microglia, Nur77 expression was reduced upon microglial activation by LPS treatment in vitro and in vivo.(344) Silencing of Nur77 enhanced inflammatory responses and overexpression or activation of Nur77 with the agonist cytosporone B (Csn-B, 68) suppressed pro-inflammatory responses.(344) These anti-inflammatory effects were shown to involve Nur77-mediated inhibition of IκB-α phosphorylation and NFκB repression.(345) Additionally, anti-inflammatory and antioxidant stress effects of Nur77 activity were demonstrated with Csn-B (68) counteracting MPP+-induced inflammation in vitro,(345) and with C-DIM5, a Nur77 and Nurr1 activating compound, diminishing NFκB activity in MPTP/TNF/IFN-treated astrocytes.(343) Of note, Popichak et al. detected compensatory expression of Nur77 and Nurr1 in astrocytes by knocking down either nuclear receptor by RNA interference (RNAi), whereas NOR-1 expression was not affected.(343) Therein, the anti-inflammatory effect of C-DIM5 increased upon Nur77 knockdown, pointing rather toward Nurr1-mediated effects. Double knockdown of both receptors fully prevented the anti-inflammatory activity of C-DIM5. However, direct binding of C-DIM5 to either receptor is only supported by molecular docking studies.
2.7.1.3. Nur77 in Multiple Sclerosis
In the context of MS, Nur77 is expressed during early T cell activation and acts as a key regulator of T cell immunometabolism, which controls the development of aberrant pro-inflammatory T cell responses and autoimmunity.(346) Nur77 deficiency led to enhanced T cell proliferation, and Nur77 knockout in EAE in mice caused earlier disease onset and significantly increased the clinical EAE score.(346) Based on Nur77’s role as a negative regulator of microglial activation, the Nur77 agonist Csn-B (68) was studied in EAE in mice. Treatment with 68 markedly ameliorated disease progression in wild-type mice but not in Nur77 knockout animals and protected from demyelination.(347) As Nur77 restricts T cell activation and T cell-mediated CNS autoimmunity, and acts as regulator of metabolic genes in activated T cells, selective Nur77 agonists may emerge as a new approach to counteract T cell-mediated autoimmune diseases like MS.
2.7.1.4. Nur77 in Alzheimer’s Disease
In AD, there is little evidence for an involvement of Nur77 to date. Expression of alpha 1-antichymotrypsin/serpinA3, a member of the serine protease inhibitor family, was found to be induced by Nur77 as it contains a Nur77 monomer response element in its promoter region.(348) It is involved in acute phase and inflammatory responses but is also known to contribute to the development of AD as it interacts with Aβ peptide and turned out to be a major component of Aβ plaques. Moreover, RXRα and Nur77 were found to translocate from the nucleus to the mitochondria in neurons after Aβ and H2O2 treatment which resulted in apoptosis.(349) Accordingly, treatment with the RXR agonist 9-cis RA (43) reduced apoptosis by blocking the translocation in vitro and in vivo and enhanced B-cell lymphoma 2 (Bcl-2) protein expression.
2.7.1.5. Nur77 Ligands
Although Nur77 is an orphan nuclear receptor, several studies have reported Nur77 modulating small molecules (Scheme 7). Growing evidence from crystal structures supports the assumption of a blocked canonical ligand binding pocket since all known Nur77 ligands to date bind to noncanonical sites on the surface of the LBD (Figure 3d). Among them, the agonist cytosporone B (Csn-B, 68), a natural product, was the first compound shown to directly bind to the Nur77 LBD(350) by glutathione S-transferase-pull-down, circular dichroism (CD) spectroscopy, surface plasmon resonance (SPR) binding kinetics, and mutagenesis studies. Two different reporter gene assays in BGC-823 cells, a human gastric cancer cell line, confirmed transactivation of Gal4-Nur77-full-length (fl) (EC50 0.278 nM) and Gal4-Nur77-LBD (EC50 0.115 nM) constructs. No response was observed with Gal4-Nur77-DBD and Gal4-Nur77-Y453A mutant constructs supporting a direct interaction with the Nur77 LBD. In addition to Nur77, binding of Csn-B (68) to the related receptor Nurr1 was observed in NMR perturbation studies, but Nurr1 transactivation by Csn-B (68) was weak.(350,351) Csn-B (68) was also evaluated in vivo where it increased blood glucose levels and induced gluconeogenic genes in wild-type animals but not in Nur77–/– knockout mice. Additionally, Nur77-induced apoptosis by targeted translocation from nucleus to cytoplasm was observed upon treatment of BGC-823 cells with Csn-B (68). Many further studies(352,353) focused on the anticancer activity of Csn-B (68), and systematic structure–activity relationship (SAR) studies on the Csn-B (68) scaffold were conducted which identified the alkyl ester function as a key pharmacophore feature for Nur77 transactivation.(352) Recently, a cocrystal structure (pdb 6KZ5) of Nur77 in complex with Csn-B (68) revealed an unusual pocket at the dimer interface between two LBD molecules(353) (Figure 3d, purple site).

Scheme 7

Scheme 7. Nur77 Ligands Reported in the Literature(325,330,350,354,356,357)
Following the discovery of Csn-B (68) as a direct Nur77 agonist, several derivatives were developed and intensively studied for their modes of action. Effects in the field of metabolic diseases were further investigated in vitro and in vivo with ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA, 69),(325) a neutral antagonist derived from Csn-B (68) with no effect in a Nur77 reporter gene assay. A cocrystal structure (pdb 3V3Q) demonstrated direct binding to two different sites on the surface of the Nur77 LBD. Site A is located between helices 4, 11, and 12 (Figure 3d, orange site), while site B constitutes a cavity on the surface close to helices 1, 5, and 8 (Figure 3d, blue site).
A potential anti-inflammatory compound was developed with the Csn-B (68) derivative n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl)phenyl]acetate (PDNPA, 70),(330) a competitive inhibitor of the Nur77–p38α interaction via binding to Nur77. The compound prevented phosphorylation of Nur77 and but conserved the ability of Nur77 to inhibit NFκB activity by direct interaction with the NFκB subunit p65 (Figure 4b). Despite also binding to the Nurr1- and NOR-1-LBDs, PDNPA (70) antagonized an NFκB reporter gene assay in a RAW264.7 murine macrophage cell line only in a Nur77-dependent fashion with an IC50 value of 1.6 μM. Ligand binding of PDNPA (70) to Nur77 was confirmed by a cocrystal structure (pdb 4RZG), which revealed binding to site A like TMPA (69), between helices 4, 11 and 12, but PDNPA (70) and TMPA (69) differed in their in vitro and in vivo activities.

Figure 4

Figure 4. NR4A receptor mechanisms of action. (a) The constitutively active NR4A receptors (Nur77, Nurr1, and NOR-1) can directly bind to specific response elements as a homodimer, as a heterodimer with RXR (only Nur77 and Nurr1), or as a monomer. Sumoylation of the respective NR causes monomerization, and these monomers activate NBRE. NR4A homodimers bind to NurRE, while NR4A:RXR heterodimers bind to DR5 response elements. (b) Additionally, Nurr1 monomers directly interact with p65 on the NFκB RE upon sumoylation and recruit the CoREST corepressor complex, which results in suppression of NFκB-regulated pro-inflammatory genes. Abbreviations: CoREST, REST corepressor; DR5, direct repeat spaced by five nucleotides; NBRE, NGFI-B responsive element; NFκB, nuclear factor-κB; NOR-1, neuron derived orphan receptor 1; NurRE, Nur response element; Nurr1, nuclear receptor related-1 protein; RXR, retinoid X receptor.

Another Csn-B (68) derivative with anticancer activity is 1-(3,4,5-trihydroxyphenyl)nonan-1-one (THPN, 71).(354) A cocrystal structure (pdb 4JGV) revealed binding to the Nur77 LBD surface between helices 5, 7, 8, 9, and 10 (Figure 3d, teal site), where also the close analogue 1-(3,5-dimethoxyphenyl)decan-1-one (DPDO, pdb 4KZI) bound but without protruding toward the subpocket between helices 5 and 7. THPN (71) induced a mitochondrial signaling pathway toward autophagic cell death and was, hence, characterized in cell viability tests in several melanoma and non-melanoma cancer cell lines, in binding studies and in knockdown experiments, while Nur77 transactivation has not been studied. A small SAR evaluation with six THPN (71) derivatives differing in chain length and hydroxyl group substitution pattern revealed a correlation between LBD binding affinity and potency, and resulted in an optimized descendant with C9 instead of C8.(355)
The pentacyclic triterpene celastrol (72) was discovered in a screening of anti-inflammatory natural products in an SPR assay for Nur77 binding where it exhibited a Kd value of 0.29 μM.(356) Binding was confirmed by CD and HPLC analysis, and celastrol (72) reduced transcriptional activity of Nur77 in a reporter gene assay at 0.5 μM in HEK293T cells. Mechanistic investigation revealed enhanced Nur77 mitochondrial translocation to inhibit inflammation via autophagy by direct interaction with a LxxLL motif of TNF receptor-associated factor 2 (TRAF2). Molecular docking studies suggested a similar binding site for celastrol (72) as shown for THPN (71). Isoalantolactone (73) was derived from a natural-product-based small molecule library screen as another Nur77-modulating compound.(357) Two different reporter gene assays in human pancreatic MiaPaCa2 cells and murine 3T3-L1 preadipocytes revealed inverse Nur77 agonism of isoalantolactone (73). By additionally activating AMPKα, the compound exhibited a dual mechanism which collectively inhibited adipogenesis in vitro and in vivo. However, direct interaction of isoalantolactone (73) with Nur77 and its binding site remain elusive.
Early findings on potential endogenous Nur77 ligands were reported by Vinayavekhin et al.(358) who discovered unsaturated fatty acids, namely, arachidonic acid and DHA (45), as Nur77 binders in a metabolomics approach from brain and testes samples. Evidence for binding was reported from an 8-anilino-1-naphthalenesulfonic acid (ANS) displacement assay and from CD experiments with the His6-Nur77 LBD. Prostaglandin A2 (PGA2, 92)(359) was later identified as another potential endogenous agonist for Nur77, and addition of biotinylated PGA2 (92) to recombinant Nur77 protein revealed binding with a Kd value of 2.05 μM according to Western blot analysis and an SPR assay. Covalent interaction of PGA2 (92) with Cys566 was postulated based on covalent molecular docking and molecular dynamic simulation based on the observation that only PGs with an endocyclic Cβ electrophile bound to Nur77. A full-length Nur77 reporter gene assay with a NurRE response element in human bronchial epithelial NHBE cells revealed dose-dependent activity with up to 15-fold Nur77 transactivation at 10 μM PGA2 (92). In line with this, we have recently discovered NSAIDs as Nur77 and NOR-1 modulators with meclofenamic acid (85) acting as Nur77 agonist, and meloxicam, lornoxicam, mofezolac, oxaprozin (83), and parecoxib (84) as inverse Nur77 agonists in a Gal4-Nur77 hybrid reporter gene assay in HEK293T cells.(360) In addition, amodiaquine (AQ, 75) and chloroquine (CQ, 76), initially characterized as Nurr1 modulators, revealed Nur77 and NOR-1 agonism in the same setting. These findings of similar ligand activities on Nur77, Nurr1, and NOR-1 suggest that obtaining selective ligands for the individual NR4A receptors will be challenging.
The antimetabolite 6-mercaptopurine (6-MP, 91), a well-known anticancer agent, was extensively studied as a Nurr1(361) and NOR-1(362) agonist and found to modulate the receptors through the AF-1 region. Nur77 activation by 6-MP (91) is hence thought to follow a similar mechanism. 6-MP (91) strongly activated Nur77 in a full-length reporter gene assay using a homodimer responsive reporter construct in C2C12 murine myoblast cells.(362) However, this activity was accompanied by an induction of Nur77 and other NR4A protein levels suggesting nonspecific effects of 6-MP (91).(363) Fangchinoline,(364) a bisbenzyltetrahydroisoquinoline alkaloid from Stephania tetrandra, modulated Nur77 through the N-terminal region, too, and inhibited Nur77 transactivation in MiaPaCa-2 cells. The natural product exhibited anticancer activity in part via inducing Nur77-dependent pro-apoptotic pathways, whereas no translocation from the nucleus occurred.
Nur77 modulation by the compound series of 1,1-bis(3′-indolyl)-1-(p-phenyl)methane (C-DIM) and analogues is controversial.(365−367) Activating (DIM-C-pPhOCH3, C-DIM5)(367) and inhibiting (DIM-C-pPhOH, C-DIM8)(366) compounds have been reported from this series and were investigated in various types of cancer cell lines. The compounds exhibited Nur77-independent apoptosis induction, kinase induction, and endoplasmic reticulum stress activation, but conclusive evidence for direct modulation of NR4A receptors is missing. The authors of C-DIM characterization as putative NR4A ligands conclude that the modulating activity on Nur77 may be due to indirect activation or deactivation rather than ligand binding.(367) Despite some evidence for direct binding from pull-down assays and CD spectroscopy, no IC50 or EC50 values for C-DIM and analogues are available, and their effects vary significantly depending on the cell context.(365) Effects of C-DIM and analogues reported from animal models are hence difficult to interpret and cannot be related to a clear mode-of-action.
Three further compounds have been reported in the context of Nur77 which do not directly bind to or interact with Nur77 but affect its activity by other mechanisms. 1,3,7-Trihydroxy-2,4-diprenylxanthone (CCE9)(368) and the anticancer agent cisplatin(369) were found to induce Nur77 protein expression, which may have similar effects as Nur77 activation owing to the high constitutive transcriptional activity of Nur77. Z-ligustilide,(370) a phthalide compound from Radix Angelica sinensis, is characterized as an autophagy inhibitor that restored Nur77 from selective degradation by autophagy, thereby enabling Nur77–Ku80 interaction which suppressed double-strand break repair. As a consequence, cell sensitivity to tamoxifen was enhanced in an autophagy-associated fashion.
2.7.1.6. Conclusion
The orphan nuclear receptor Nur77 is an emerging target in several indications including neurodegenerative diseases (summarized in Table 7). Despite ubiquitous expression as well as pleiotropic and nontranscriptional effects, a role of Nur77 in neuroinflammation and dopamine neurotransmission is well described. Validation of Nur77 as a therapeutic target will require multiple further studies, however, which are hindered by the lack of high-quality tool compounds. The unclear mode-of-action, lacking proof for direct interaction, and poor selectivity of C-DIM-based Nur77 modulators compromises the significance of several studies on Nur77 in neurodegeneration. Selective Nur77 agonists and inverse agonists with confirmed direct binding are needed for a deeper understanding of Nur77 in neurodegeneration. Future studies should also further analyze the nongenomic effects involving translocation of Nur77 and whether this pathway can be selectively modulated with ligands.
Table 7. Summarized Observations on Nur77 in Neurodegeneration
Nur77 (= NR4A1; also known as NGFI-B, TR3, NAK-1, and N10)
Nur77 in ADAlpha 1-antichymotrypsin/serpinA3 is involved in AD development and Nur77 regulated.(348)
Translocation of Nur77-RXR to mitochondria in neurons upon Aβ/H2O2 treatment results in apoptosis.(349) Activation with the RXR agonist 9-RA (43) prevented translocation, reduced apoptosis, and enhanced Bcl-2 expression in vitro and in vivo.(349)
Nur77 in PDNur77 knockout slightly enhanced basal locomotor activity in mice and rats.(334,335)
Nur77 knockout in mice: TH ↑, dopamine metabolite DOPAC ↑, COMT ↓.(334)
Nur77 knockout in the MPTP PD model had conflicting results: sensitization to dopaminergic cell death(340) and decreased dopaminergic neuronal loss after perturbation.(335)
Nur77 knockout in the 6-OHDA PD model decreased dopaminergic neuronal loss in rats.(335)
Nur77 was downregulated in MPTP in monkeys and in the nigrostriatal region of mice.(339,340)
6-OHDA treatment induced Nur77 expression in vitro(342) and in vivo.(335) Nurr1 was counter-regulated.
Microglial activation by LPS treatment reduced Nur77 expression in vitro and in vivo (MPTP model).(344)
Nur77 activation (Csn-B (68) or C-DIM5) suppressed NFκB activity in BV2 microglia and counteracted inflammation in vitro.(343−345)
Nur77 in MSNur77 knockout enhanced T cells activation and T cell-mediated CNS autoimmunity in vitro and in vivo.(346)
Nur77 knockout in EAE caused earlier disease onset and increased EAE score/severity.(346)
Nur77 activation (Csn-B (68)) ameliorated EAE progression and protected from demyelination in wild-type mice but not in Nur77 knockout animals.(347)

2.7.2. Nurr1 (NR4A2)

2.7.2.1. Overview
The orphan nuclear receptor related 1 (Nurr1) is the second member of the NR4A subfamily and was initially considered as a ligand-independent transcription factor. The first crystal structure (pdb 1OVL) of the NR4A family in 2003 revealed Nurr1 in apo form in an autoactivated conformation and lacking a canonical ligand binding site due to tightly packed bulky hydrophobic residues within the LBD core(317) (compare Figure 3c). Moreover, structural analysis identified a hydrophobic coregulator interaction surface between helices 11 and 12 distinct from the canonical nuclear receptor coactivator interaction site, which in turn is a highly polar area in the Nurr1 LBD.(371,372) These early findings indicated different regulatory mechanisms and a potentially different coregulatory network for Nurr1. In line with this, we observed ligand-dependent displacement of four coregulator peptides by inverse Nurr1 agonists, namely, NCoR-1 and SMRT, considered as corepressors, the coactivator NCoA6 and the coregulator NRIP1.(360) Additionally, the SUMO-E3 ligase PIASγ is known as a potent repressor of Nurr1 transactivation.(373) Like its relative Nur77 (see section 2.7.1), Nurr1 can act as a monomer (on the NBRE), a homodimer (on the NurRE), and a heterodimer with RXR (on the DR5) on different response elements(319−321) (Figure 4a). Nurr1 is the most extensively studied NR4A member in the context of neurodegenerative diseases. It is mainly expressed in the central nervous system with particularly high abundance in mesencephalic dopaminergic neurons of the ventral tegmental area and substantia nigra pars compacta, and the paraventricular thalamic nuclei.(322) As a key regulator in dopaminergic neuron development and maintenance, Nurr1 is expressed in the midbrain from early prenatal state to adulthood.(374) Nurr1 regulates genes that are essential factors in dopamine neurotransmission such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and aromatic l-amino acid decarboxylase (AADC).(374−377) Various Nurr1-regulated genes were discovered in dopaminergic neurons including Dlk1, Ptpru, and Klhl1,(378) the GTP cyclohydrolase,(379) vasoactive intestinal peptide (VIP),(380) receptor tyrosine kinase Ret(381) critical in neurotrophic factor signaling, and topoisomerase IIβ,(382) but also osteopontin, osteocalcin, and neuropilin(29) are Nurr1-dependent. Although Nurr1 is considered as a contributing factor in attention-deficit hyperactivity disorder,(383) inflammatory arthritis,(384) metabolic disease, and cancer (reviewed in ref (385)), emerging evidence ascribes Nurr1 a particularly important role in the pathogenesis of neurodegenerative diseases and presents as a very promising drug target especially in PD.
2.7.2.2. Nurr1 in Parkinson’s Disease
The key regulatory role of Nurr1 in dopaminergic neuron development became apparent in knockout studies, as homozygous Nurr1 knockout mice exhibited a complete loss of ventral mesencephalic dopaminergic neurons, altered gene expression in the dorsal motor nucleus of the brainstem, respiratory dysfunction, and notable hypoactivity, and died within two days after birth.(29,374) Moreover, a number of Nurr1 SNPs were found in patients with familial PD.(29,386) Most notably, the polymorphism rs35479735 located in intron 6 of the Nurr1 gene, which may affect the splicing process, strongly correlates with an increased risk of sporadic and familial PD.(387) Post-mortem analysis of PD patients revealed a significant decrease of Nurr1 expression in nigral neurons containing α-synuclein inclusions, which correlated with loss of TH+ neurons.(388) Accordingly, diminished levels of Nurr1 were also found in nigral dopaminergic rat neurons caused by elevated α-synuclein levels(389) and in MPTP-treated mice.(390) In contrast, Nurr1 overexpression protected dopaminergic neurons against several toxic insults in vitro and in vivo, which was apparent from upregulation of neuroprotective genes and increased neuronal survival.(389−392) Moreover, transplantation of mesenchymal stem cells with lentiviral Nurr1 overexpression in 6-OHDA-treated rats increased the number of TH+ neurons, lowered microglial activation, and reduced expression of inflammatory mediators in the substantia nigra.(393) In microglia and astrocytes, Nurr1 acted as a negative regulator of NFκB-regulated inflammatory genes by stabilizing the CoREST corepressor complex at p65/p50 cis-acting promoter elements(394) (Figure 4b) and thereby limited the production of neurotoxic mediators like TNFα, IL-1β, and iNOS in the substantia nigra of LPS-injected mice. In contrast, interaction of Nurr1 and coactivator Foxa2 in midbrain dopaminergic neurons was found to diminish the Nurr1–CoREST interaction and to induce dopamine phenotype gene expression.(395)
Despite the early assumption that Nurr1 is ligand independent, the antimalarial amodiaquine (AQ, 75) was discovered as an activator of Nurr1 and enhanced the expression of Nurr1-regulated genes (TH, DAT, VMAT2, AADC) in rat NSCs. Moreover, AQ (75) suppressed pro-inflammatory cytokine release after LPS treatment in primary rat microglia and improved behavioral deficits in 6-OHDA-lesioned rats.(396) In addition to AQ (75), the prostaglandins A1 (PGA1, 81) and E1(397) as well as the dopamine metabolite 5,6-dihydroxyindole (DHI, 82)(398) were identified as potential endogenous Nurr1 activators. PGA1 (81) and PGE1 exhibited neuroprotective effects in a primary midbrain dopaminergic neuron-glia coculture derived from rat embryos treated with MPTP or LPS, induced dopaminergic gene expression in MN9D cells in a Nurr1-dependent manner, and attenuated motor deficits in MPTP-induced PD in mice.(397) DHI (82) significantly increased mRNA expression of Nurr1-regulated genes (TH, VMAT2, and DAT) in wild-type zebrafish larvae.(398) The synthetic Nurr1 agonists SA00025 (79)(399) and IP7e (80)(400) also exhibited neuroprotective and anti-inflammatory effects in different rodent PD models. However, Nurr1 levels in the brain were also increased upon treatment with IP7e (80)(400) pointing to other mechanisms than direct Nurr1 activation.
Exploration of Nurr1–RXR heterodimer-specific RXR agonists has further validated Nurr1 activation as a valuable approach to counteract neuroinflammation and PD in vitro and in vivo. XTC0139508 (85),(401) its descendant BRF110 (86),(402) and IRX4204 (90)(403) were intensively studied in vitro for their neuroprotective effects in various neuronal cell cultures and induced Nurr1-regulated genes. Additionally, BRF110 (86)(402) and IRX4204 (90)(403) improved motor function and reduced dopaminergic neuron loss in 6-OHDA and MPTP rodent models. HX600 (87) exhibited neuroprotective effects, too, by lowering levels of pro-inflammatory mediators in LPS-stimulated primary mouse microglia and by reducing ischemic neuronal damage and impaired motor function in an ischemic stroke model in mice.(404)
2.7.2.3. Nurr1 in Alzheimer’s Disease
Beyond Nurr1’s overall neuroprotective and anti-neuroinflammatory activity, its role in AD remains to be studied in detail (recently reviewed in ref (405)). A number of studies indicates involvement of Nurr1 dysregulation as a contributing factor in the pathogenesis of AD. Two in vitro models of AD using Aβ1–42 fibril-treated cells observed downregulation of Nurr1 protein and mRNA levels in primary rat neurons and in a neuronally differentiated human mesenchymal cell line.(406) In addition, Nurr1 mRNA levels in the hippocampus were reduced in mutant APP transgenic mice as a model of early memory loss in AD.(407) Most notably, post-mortem analysis of AD patients revealed a significant decrease of Nurr1 expression in nigral neurons containing neurofibrillary tangles, which correlated with a loss of TH+ neurons.(388) In line with this, 5XFAD mice displayed Nurr1 coexpression with Aβ accumulation in the subiculum and frontal cortex at early stages, and an age-dependent loss of Nurr1-expressing cells in later stages.(408) Nurr1 knockdown by stereotactic Nurr1-shRNA injection in the subiculum amplified AD pathology in 5XFAD mice, whereas Nurr1 overexpression and Nurr1 activation with the agonist AQ (75) ameliorated AD symptoms with reduced Aβ accumulation, less neurodegeneration, and improved cognitive function.(409)
2.7.2.4. Nurr1 in Multiple Sclerosis
Studies on Nurr1 involvement in the context of MS reported contradictory findings. The Nurr1 activator IP7e (80) caused protective effects in EAE in mice by inhibiting NFκB-mediated inflammation in early disease stage.(410) Accordingly, heterozygous Nurr1 knockout mice exhibited an early EAE disease onset with elevated inflammatory infiltrates in the spinal cord.(411) In contrast, systemic RNAi-mediated Nurr1 knockdown in mice attenuated EAE, which was referred to a potential role of Nurr1 in Th17 cell differentiation via regulation of IL-21 and IL-23R expression.(412) The Nurr1 agonist chloroquine (CQ, 76) activated Treg cell differentiation from naïve murine T cells in a Nurr1-dependent manner and significantly suppressed the progression of inflammatory bowel disease, another autoimmune disease, in a dextran sulfate sodium (DSS)-induced mouse model.(413)
2.7.2.5. Nurr1 Ligands and Modulators
Although Nurr1 is considered as an orphan nuclear receptor and lacking a classical ligand-binding site, recent findings of potential endogenous ligands, evidence from cocrystal structures, and mechanistic studies revealed Nurr1 as a promising drug target. In 2015, Kim et al.(396) demonstrated that Nurr1 can be directly modulated via its LBD by small molecules and discovered the two antimalarial drugs AQ (75) and CQ (76) as Nurr1 ligands in a drug screening in a full-length Nurr1 reporter gene assay using a monomer responsive reporter construct in human neuroblastoma SK-N-BE(2)C cells (Scheme 8). Both compounds were shown to interact directly with the LBD by NMR perturbation experiments and mutagenesis studies located the interaction site close to the canonical ligand-binding pocket, which was recently confirmed by Munoz-Tello et al.(351) In addition, we have recently discovered the two AQ-derived fragment-sized Nurr1 agonists 77 and 78 which provided new insights in the activation mechanism of Nurr1 by causing recruitment of NCoR-1 and SMRT upon agonist binding.(414) Another noncanonical binding pocket within the Nurr1 LBD was first discovered for the dopamine metabolite DHI (82) which covalently bound to Cys566 in a Nurr1 cocrystal structure (pdb 6DDA) and thereby induced a pocket between helices 4, 11, and 12 involving outward movement of helix 12(398) (compare Figure 3d, orange site). In vitro, DHI (82) stimulated Nurr1 activity in a Gal4-Nurr1 hybrid reporter gene assay in human choriocarcinoma JGE3 cells by 1.6-fold at 100 μM.

Scheme 8

Scheme 8. Nurr1 Modulators Reported in the Literature(360,396−398,418,422)
First evidence for a potential endogenous Nurr1 ligand was reported for the unsaturated fatty acid DHA (45).(415) Solution NMR spectroscopy mapped the putative ligand-binding pocket close to the AQ binding site and recruitment of a PIASγ peptide was found enhanced by DHA (45) binding. Two full-length reporter gene assays using a monomer responsive reporter construct in HEK293T cells and murine dopaminergic MN9D cells showed dose-dependent repression of Nurr1 activity by ∼25% at 50 μM DHA (45). Further structural analysis by NMR experiments, deuterium uptake mass spectrometry, and molecular dynamic simulations suggested that the putative canonical ligand-binding pocket is able to expand from its collapsed conformation to harbor the unsaturated fatty acid.(416,417) Rajan et al. added two prostaglandins, namely, PGA1 (81) and PGE1, to the collection of Nurr1’s endogenous ligands(397) and found covalent binding of PGA1 (81) to Cys566 (pdb 5Y41) comparable to the ligand-binding pocket induced by DHI (82) with an even stronger 21° shift of helix 12. PGA1 (81) and PGE1 induced Nurr1 transactivation in two different reporter gene assays, Gal4-Nurr1 and full-length Nurr1, performed in murine dopaminergic MN9D cells and N27-A rat dopaminergic neurons with estimated EC50 values of 5 μM and 3 μM. In line with this, we recently discovered several NSAIDs as Nurr1 modulators.(360) Among them, the first-in-class inverse Nurr1 agonists oxaprozin (83) and parecoxib (84) counteracted intrinsic Nurr1 activity in four different reporter gene assay settings in HEK293T cells. Meclofenamic acid (85, Gal4-Nurr1 EC50 4.7 μM) evolved as a Nurr1 modulator with differential activity on different Nurr1 response elements. The NSAIDs also affected the coregulator interaction profile of Nurr1 with NCoR-1, SMRT, NCoA6, and NRIP as well as the receptor’s dimerization equilibrium in HTRF-based assays. Moreover, NSAIDs and AQ-type ligands exhibited simultaneous Nurr1 modulation with additive effects pointing to the existence of two independent binding sites within the Nurr1 LBD.
In addition to these few orthogonally validated direct Nurr1 modulators, further compounds were reported to affect Nurr1 activity for which confirmation of direct interaction is lacking. The imidazopyridine SA00025 (79)(418) has been reported as a potent and selective Nurr1 agonist based on two luciferase reporter gene assays (Gal4-Nurr1fl (EC50 218 nM)(418) and monomer responsive reporter construct (EC50 0.7 nM)(419)). The compound has favorable ADMET and pharmacokinetic properties(418,420) except for a hErg liability (IC50 1.5 μM) and was found to reach the brain of rats after oral administration where it significantly induced Nurr1-regulated gene expression in the substantia nigra after seven days of daily dosing.(399) Direct binding to Nurr1 was studied for several compounds of the SA00025 (79) series by SPR,(419) but the reported data are incomprehensive, and a direct Nurr1 binding of the lead compound SR24237(418) could not be confirmed.(351)
A benzimidazole-based combinatorial approach to Nurr1 modulators has reported SR10098(421) as one of three hits, and Nurr1 agonists with isoxazolopyridinone scaffold were derived from a high-throughput screening (HTS) campaign(422) with subsequent SAR studies. Both series reached low nanomolar potencies in a reporter gene assay in stably Nurr1-expressing MN9D cells. Among these compounds, IP7e (80, EC50 3.9 nM) showed brain bioavailability in mice(422) and was applied to the EAE(410) and a PD(400) mouse model. Data from a recent NMR structural footprinting analysis puts a direct binding of SR10098, IP7e (80), and analogue SR10658 to the Nurr1 LBD into question, however.(351)
As stated for Nur77 (see section 2.7.1), C-DIM derivatives were also extensively studied as Nurr1 modulators with contradictory results in pancreatic(423) and bladder cancer(424) cells, neuronal cells,(425−427) and glioblastoma cells.(428) Multiple anti-inflammatory and neuroprotective effects were also reported from PD mouse models.(425,427,429) Mechanistic evaluation of NR4A modulation by C-DIM derivatives using various hybrid receptor constructs in reporter gene assays demonstrated that the NH2-terminal domain was sufficient for transactivation.(423) Through N-terminal Nurr1 modulation, C-DIM derivatives may hence exhibit direct effects on Nurr1 for example in NFκB transrepression(429) (Figure 4b), but altered Nurr1 protein levels(426) and indirect mechanisms rather than direct Nurr1 transactivation via its LBD appear to dominate the effects.(351)
In addition, the antimetabolite 6-MP (91) was identified as a Nurr1 activator from an HTS utilizing a full-length reporter gene assay under the control of the homodimer responsive element in CV1 cells.(361) Closer evaluation of Nurr1(361) and NOR-1(362) modulation suggested a noncanonical mechanism of nuclear receptor activation through the N-terminal AF-1 domain not involving interaction with the LBD.
A number of other compounds, mostly chemotherapeutic agents, such as camptothecin,(430) the metabolite 7-ethyl-10-hydroxy-camptothecin of irinotecan, and KU0171309(431) (from HTS) were found to inhibit Nurr1 transactivation. Apart from KU0171309 whose mode of Nurr1 modulation remains elusive, these agents were found to suppress Nurr1 activity via inhibition of the EGFR cascade. Furthermore, neuroprotective agents have been discovered which do not directly modulate Nurr1 activity but were shown to induce Nurr1 expression in vitro and in vivo. Among them were the anti-PD drug pramipexol,(432) for which Nurr1 upregulation was proposed to be mediated via the dopamine D3 receptor, the phosphodiesterase-3 inhibitor cilostazol,(433) and moracenin D,(434) a flavonoid extracted from Mori Cortex radicis.
2.7.2.6. Nurr1-RXR Heterodimer-Specific RXR Ligands
As discussed above, Nurr1 can act as a permissive heterodimer with RXR opening another avenue to Nurr1 modulation via heterodimer activation with RXR agonists. Owing to the multitude of RXR heterodimers and associated effects, heterodimer preferential activity is very desirable in this context. Hence, a number of Nurr1–RXR heterodimer-specific RXR ligands (Scheme 9) have been reported which were shown to promote Nurr1 activity or enhance its function in PD models (outlined above). The aminopyrimidine derivative XCT0135908 (XCT, 85)(435) selectively induced luciferase activity dependent on a Gal4–Nurr1–RXRα heterodimer in CV-1 cells. Its activity was blocked by the RXR antagonist LG1208. However, XCT (85) has low plasma stability and poor brain exposure after intraperitoneal administration, and even intracerebroventricular injection failed to show in vivo activity as the expression of Nurr1 regulated genes in midbrain such as TH was not changed.(402) BRF110 (86),(402) a close analogue of XCT (85), activated a full-length Nurr1-RXRα reporter gene assay utilizing a heterodimer responsive reporter construct in the human dopaminergic neuroblastoma cell line SH-SY5Y with an EC50 value of ∼0.9 μM. Its binding to RXRα is only supported by molecular docking studies, but lentiviral knockdown of Nurr1 demonstrated involvement of Nurr1 in heterodimer activation. Pharmacokinetic properties of BRF110 (86) after intraperitoneal administration in mice were improved compared to 85 with CNS bioavailability and a moderate half-life of 1.5 h in plasma and brain. The dibenzodiazepine RXR ligand HX600 (87) was also found to selectively activate Nurr1- and Nur77-RXR heterodimers in several cellular settings.(436,437) The chiral dihydrobenzofuran 88(438) was designed as a full RXR agonist from a series of conformationally constrained RXR ligands with a slight (3-fold) preference for the Nurr1–RXR heterodimer (pEC50 7.9, 111% efficacy) compared to the RXR homodimer (pEC50 7.6, 85% efficacy) in a bioluminescence resonance energy transfer (BRET) assay. Cocrystal structure analysis of RXRα in complex with dihydrobenzofuran 88 and the TIF2 coactivator peptide (pdb 5EC9) confirmed orthosteric binding to RXR and a typical agonist conformation. The synthetic honokiol derivative 89 with a biaryl scaffold demonstrated a greater 25-fold selectivity for the Nurr1-RXRα heterodimer (pEC50 9.1, 129% efficacy) compared to the RXRα homodimer (pEC50 7.7, 291% efficacy) determined in a BRET assay.(439) The respective cocrystal structure analysis indicated that compact ligands, allowing movement of helix 7 and 11, favor RXRα heterodimerization with Nurr1 (pdb 5MKU), whereas ligands with substituents in the 2′ position on the biaryl scaffold induced pocket expansion with helix 12 movement, resulting in lower binding affinity or antagonistic behavior (pdb 5MKJ) and promoting RXRα homodimerization.

Scheme 9

Scheme 9. Nurr1-RXR Heterodimer-Specific RXR Agonists Reported in the Literature(402,403,435,436,438,439)
The RXR ligand IRX4204 (90) has been studied most extensively in the context of neurodegeneration. Profiling of IRX4204 (90) demonstrated potent induction of Nurr1-dependent transcriptional activity (EC50 < 1 nM) in COS7 cells transfected with full-length Nurr1 and RXRα constructs and, surprisingly, a monomer responsive (NBRE) reporter construct.(403) Pharmacokinetic parameters (determined in rats) of IRX4204 (90) were favorable with bioavailability in the brain at reasonable concentrations (11.5 ± 2.9 nM) after oral administration of IRX4204 (90), which was sufficient to induce Nurr1-regulated gene expression in the substantia nigra. In addition to IRX4204 (90), also the most widely used RXR agonist bexarotene (42) was found to favor the Nurr1-RXR heterodimer (pEC50 8.3) over the RXR homodimer (pEC50 7.5) in a BRET assay in HEK293T cells.(440) In vivo experiments demonstrated that bexarotene (42) upregulated Nurr1-dependent genes DAT and VMAT2, rescued dopaminergic neuronal loss, and reversed behavioral deficits in 6-OHDA-lesioned rats. However, the neuroprotective effects of bexarotene (42) cannot be ascribed to Nurr1-mediated effects alone as the LXR–RXR and PPAR–RXR heterodimers are also effectively activated by bexarotene (42). Volakakis et al.(391) observed no effect of bexarotene (42) on dopamine neuron loss and motor impairment in 6-OHDA-injected rats but found bexarotene (42) able to restore disrupted Ret expression and neurotrophic GDNF signaling.
2.7.2.7. Conclusion
Nurr1 is an emerging drug target being extensively studied in the context of neurodegenerative diseases (summarized in Table 8) in which it holds enormous potential as a key regulator of dopaminergic neuron function. However, the available Nurr1 modulator tools are of insufficient quality to fully explore the potential of Nurr1 modulation, and the limited quality of (putative) Nurr1 modulators used in preclinical studies weakens the significance of these experiments. More potent, more selective, and particularly better characterized tools are needed for pharmacological validation of Nurr1 in neurodegeneration and other pathologies. Pending further validation of Nurr1 as a therapeutic target, potent and selective Nurr1 agonists may hold remarkable potential as a disease-modifying approach especially in PD.
Table 8. Summarized Observations on Nurr1 in Neurodegeneration
Nurr1 (= NR4A2; also known as NOT, TINUR, and HZF-3)
Nurr1 in ADNurr1 expression in nigral neurons was found diminished in AD patients.(388)
Nurr1 mRNA levels in the hippocampus were decreased in APP transgenic mice.(407)
Nurr1 was coexpressed with Aβ accumulation in the subiculum and frontal cortex in early-stage 5XFAD mice.(408)
5XFAD mice lose Nurr1 expressing cells in an age-dependent fashion.(408)
shRNA-mediated Nurr1 knockdown in the subiculum worsened AD pathology in 5XFAD mice.(409)
Nurr1 overexpression or activation (AQ (78)) improved AD symptoms (Aß ↓, neurodegeneration ↓, cognitive function ↑) in 5XFAD mice.(409)
Nurr1 in PDNurr1 knockout caused loss of dopaminergic neuron development and respiratory dysfunction and is lethal.(29,374)
Nurr1 expression in nigral neurons was found decreased in PD patients and in rodent models of PD.(388−390) Diminished Nurr1 levels correlated with high α-synuclein levels and loss of TH+ neurons.(388−390)
Nurr1 overexpression protected neurons against toxic insults of α-synuclein in vitro and in rodent PD models.(389−393)
Nurr1 agonists upregulated neuroprotective and dopaminergic genes in vitro and in vivo.(396−398,403,414)
Nurr1 agonists decreased expression of pro-inflammatory cytokines in vitro.(396,397,404)
Nurr1 agonists and heterodimer-specific Nurr1-RXR agonists exhibited neuroprotective effects and improved symptoms in 6-OHDA-induced PD in mice and rats(396,399,401−403) and attenuated motor deficits in MPTP-treated mice.(397,402)
Nurr1 in MSHeterozygous Nurr1 knockout caused early EAE onset and enhanced inflammatory infiltrates in the spinal cord.(411)
Systemic Nurr1 knockdown attenuated EAE via diminished Th17 cell differentiation.(412)
Nurr1 activator IP7e (80) had protective effects in EAE by decreasing NFκB activity.(410)

2.7.3. NOR-1 (NR4A3)

2.7.3.1. Overview
The neuron derived orphan receptor 1 (NOR-1, NR4A3) is a very poorly studied NR, whose developmental and physiological functions remain widely elusive.(441) As third member of the NR4A subfamily, it shares many characteristics of the other two members of this family, with the exception that NOR-1 appears not to form heterodimers with RXR in contrast to Nurr1 and Nur77(385) (compare Figure 4a). Similar as for Nur77 and Nurr1, structural analysis of NOR-1 suggested that the receptor lacks an accessible ligand binding pocket. NOR-1 adopts a self-activated conformation in the absence of a ligand to be constitutively active (compare Figure 3c). Its transcriptional activity hence primarily depends on the expression level.(442) NOR-1 mRNA is expressed in many rodent tissues. A notably high abundance was observed in the developing rat brain, whereas NOR-1 levels in the adult brain were lower.(443) NOR-1 is mainly expressed in the cerebral neocortex, hippocampus, amygdala, cerebellum, and dopaminoceptive areas, for example, striatum, nucleus accumbens, olfactory tubercle, and prefrontal and cingular cortices.(443,444) In contrast, NOR-1 mRNA levels in dopaminergic neurons of the midbrain are low.(443) Additionally, NOR-1 is present in the neuronal cytoplasm throughout the brain and spinal cord.(443) Although one study has reported NOR-1 knockout as embryolethal,(385,445) most knowledge on the therapeutic potential of the orphan receptor results from knockout studies.
2.7.3.2. NOR-1 and Neurodegeneration
According to the scarce available knowledge, NOR-1 is involved in inflammation, vascular biology, immunity, and lipid and glucose metabolism, suggesting that dysregulation of NOR-1 could lead to diseases such as obesity, diabetes, cardiovascular disease, and cancer.(442) In addition, some preliminary evidence indicates that NOR-1 might be involved in the pathogenesis of neurodegenerative diseases. NOR-1 was found to play an important role during development of the CNS by mediating neuronal differentiation and maintaining neuronal plasticity in the adult CNS.(441) In mice, NOR-1 knockout led to impaired axonal growth in the hippocampus, postnatal neuronal cell death, and a compact pyramidal cell layer of Ammon’s horn was not formed at CA1 and CA3 in NOR-1–/– mice.(441) This suggests a specific role for NOR-1 in the survival of CA1 pyramidal cells.(441) In addition, an increased liability to limbic seizures as well as a compromised axonal guidance in the dentate gyrus and in the mossy fibers were observed in NOR-1 knockout mice.(443) Further important evidence for an involvement of NOR-1 in neurodegenerative diseases evolves from its accumulation in Lewy bodies of patients with PD and dementia with Lewy bodies (DLB), and in glial and neuronal cytoplasmic inclusions in multiple system atrophy (MSA).(443) Moreover, NOR-1 induced the anti-apoptotic protein cIAP2 in neuronal cells under oxidative stress, hypoxia, and ischemia(446) and was upregulated by the transcription factor cAMP response element binding protein (CREB) which is considered as an important factor for neuronal survival and neuroprotection.(392) CREB-regulated expression of NOR-1 and the other NR4A receptors was detected in neuronal cells, raising the assumption that the NR4A family receptors function as mediators of CREB-induced neuroprotection and neuronal survival.(392,446)
2.7.3.3. NOR-1 Ligands and Modulators
NOR-1 is classified as an orphan nuclear receptor, and no potent ligand for NOR-1 has been discovered so far. Two NOR-1-activating compounds have been reported in the literature, the anti-inflammatory and antineoplastic drug 6-MP (91)(362) and the eicosanoid prostaglandin A2 (PGA2, 92).(447) PGA2 (92) was shown to bind to the NOR-1 LBD and to activate NOR-1-dependent gene transcription at 10 μM concentration.(447) PGA2 (92) activated the full-length NOR-1 in the presence and absence of RXRα, indicating that RXRα was not necessary for its activity, which agrees with the assumed monomeric activity of NOR-1.(447) Furthermore, it was shown that a NOR-1 mutant lacking the LBD was not activated by PGA2 (92).(447) The effect exerted by PGA2 (92) on NOR-1 is rather weak, however. In contrast to PGA2 (92), which likely activates NOR-1 through its LBD, 6-MP (91) required the N-terminal AF-1 domain for NOR-1 activation.(362) More specifically, the region between amino acid residues 1 and 150 mediated the NOR-1 activation by 6-MP (91).(362) In a Gal4-NOR-1-AF-1-assay, 6-MP (91) achieved a strong 113-fold NOR-1 activation at 50 μM in proliferating murine C2C12 myoblasts.(362) The 6-MP analogues 6-mercaptopurine riboside (93) and 6-mercaptopurine deoxyriboside (94) also activated the N-terminal NOR-1 region.(362)
2.7.3.4. Conclusion
NOR-1 is a very poorly studied orphan nuclear receptor, and little is known about its therapeutic potential (summarized in Table 9). Knockout studies provide preliminary evidence that NOR-1 is involved in neuronal cell survival and might therefore be an attractive target in neurodegenerative diseases. Particularly, the observed accumulation of NOR-1 in Lewy bodies of PD patients and in neuronal cytoplasmic inclusions in MSA as well as its function as a mediator of CREB-induced neuroprotection support this assumption. However, only observations on decreased NOR-1 activity (knockout) are available so far since potent and selective NOR-1 activators are lacking. NOR-1 agonist and inverse agonist tools are urgently required to capture the orphan receptor’s potential in neurodegenerative diseases.

Scheme 10

Scheme 10. NOR-1 Activating Compounds
Table 9. Summarized Observations on NOR-1 in Neurodegeneration
NOR-1 (= NR4A3; also known as TEC, MINOR, and CHN)
NOR-1 in neurodegenerationNOR-1 knockout in mice(441) impaired axonal growth in hippocampus, caused postnatal neuronal cell death, and compromised axonal guidance in dentate gyrus and mossy fibers.
NOR-1 expression is enhanced by the stress-induced transcription factor CREB, which is an important factor for neuronal survival and neuroprotection.(392,446)

2.8. Estrogen receptors (ER, NR3A)

2.8.1. Overview

Estrogen receptors (ER)(448−450) comprise two subtypes ERα and ERβ (ERα, NR3A1; ERβ, NR3A2), which together with the G protein coupled estrogen receptor GPER mediate the effects of estrogens and estrogenic compounds. Although estrogens are primarily female hormones, ERs are crucial transcription factors not only in females but have relevance also in males as illustrated by the infertility of male ERα knockout mice.(449−451) With ER agonists as part of contraceptives and ER antagonists as well as the selective ER modulators (SERMs) as anticancer drugs, ERs have considerable relevance as drug targets.(448,449) ERs are found in female reproductive organs, as well as in bone, brain, liver, colon, skin, and salivary gland with different subtype distributions.(448,449) Although ERα and ERβ share high structural similarity, selective targeting has been achieved with synthetic ligands.(448,449) As steroid receptors, ERs act as homodimers on their response element ERE (GGTCAnnnTGACC) but also exhibit other mechanisms of activity including indirect interaction with the DNA via binding to other transcription factors (“tethering”) as well as rapid nongenomic effects.(448−450) The fact that several neurodegenerative and neuroinflammatory diseases (e.g., MS, AD) have a higher incidence in women(452,453) may suggest an involvement of sexual hormones in their pathogenesis and point to a potential role of ERsas pharmacological targets in neurodegeneration. Mainly based on epidemiological observations, postmenopausal decline in estrogen levels is hypothesized as a potential link to higher prevalence of AD in women.(452,454) Additionally, evidence for an association between ER variants and AD has been reported.(455) ER modulation, therefore, is considered as promising therapeutic strategy particularly in age-related neurodegenerative diseases.(454)

2.8.2. ER in Alzheimer’s Disease

The mechanisms by which estrogens contribute neuroprotective, anti-neuroinflammatory, and anti-neurodegenerative effects are multifaceted. In vitro, estrogens protected cultured neurons against several toxic insults including oxidative stress, excitotoxicity, and Aβ-mediated toxicity.(456−461) These effects were shown to be at least in part dependent on ER activation(459,462,463) and to involve ER-mediated induction of Bcl-2 proteins(464) that promote cell survival. Neuroprotective effects were individually demonstrated for both ER subtypes. In cultured rat cortical neurons, selective ERβ activation was sufficient for neuroprotective effects against Aβ,(465) while in SH-SY5Y neuroblastoma cells, ERα activation protected against Aβ toxicity also in the absence of ERβ.(466) Estrogens also exhibited neuroprotective effects in several rodent models of neurotoxicity,(459,467−470) which could be linked to ER activation.(459) While some observations point to a more prominent role of ERα in neuroprotection,(471,472) activation of both ER subtypes exhibited similar neuroprotective effects in several studies, and their individual contributions have not been elucidated.(473−475) The signaling pathways of ERα- and ERβ-mediated neuroprotection seem to differ,(454,466,472,473,476−478) however, suggesting potentially additive effects for activation of both isoforms. Additionally, extranuclear mechanisms of ERs have been reported to involve in neuroprotection(479) among which mitochondrial activities of ERβ seem to be of particular importance.(480) Estrogens were also found to decrease Aβ formation and to promote its clearance in several studies,(481−487) whereas estrogen deficiency in the brain enhanced plaque formation in a transgenic AD mouse model.(488) Estrogen effects on Aβ levels likely involve ER-mediated upregulation of degrading enzymes (insulin-degrading enzyme and neprilysin),(454,489) but experimental observations also indicate participation of rapid, nongenomic mechanisms.(481−486) A recent in vitro study(490) has shown that ERβ activation with diethylpropionitrile or ERβ overexpression can promote autophagy of extracellular Aβ, while ERβ silencing had the opposite effect.

2.8.3. ER in Parkinson’s Disease

In the context of PD, which in contrast to AD and MS has a higher prevalence in men,(491) effects of estrogen use are controversial,(492−495) and clinical trials(496,497) have failed to demonstrate pronounced therapeutic efficacy of estrogens despite the broad evidence for neuroprotective activity of ER activation in other pathologies. Preclinical studies observed sex differences in estrogen effects in rodent PD models and varying efficacy depending on the treatment start, suggesting that the response to estrogens in the brain is lost over time and that estrogen therapy may have protective effects only when applied during early menopause.(495) Alterations in brain ER levels might hence affect treatment outcomes.(495) Use of ER agonists or SERMs in most rodent PD models was not associated with therapeutic effects,(495,498−500) and only few studies have reported beneficial activities of ER modulation in PD. In 6-OHDA-induced disease in rats, AC-186 (95), a selective ERβ agonist counteracted the loss of dopaminergic neurons in the substantia nigra, cognitive impairment, and motor deficits.(501) Interestingly, AC-186 (95) was superior to 17β-estradiol (96), suggesting an advantage of ERβ selectivity, and the beneficial effects were only present in male animals. Baraka et al.(500) applied different types of ER ligands to 6-OHDA-induced PD in rats. They report therapeutic effects as determined by behavioral observations and biochemical parameters for 17β-estradiol (96), the selective ERα agonists propylpyrazoletriol (PPT, 97), and the SERM raloxifene (98), while the ERβ selective agonist diarylpropionitrile (DPN, 105) and tamoxifen (99) were not active. Overall, strong evidence for ERs as promising targets for PD is lacking.

2.8.4. ER in Neuroinflammation and Multiple Sclerosis

Estrogens also exhibit pronounced anti-neuroinflammatory activity which is mainly attributed to their effects on astrocytes and microglial cells.(453,502−505) ER agonists suppressed the release of pro-inflammatory cytokines after LPS stimulation from primary human astrocyte cultures(506) and inhibited LPS-induced astrocyte activation in rats.(507) Effects of estrogens and ER agonists have hence been broadly studied in the context of MS. Estrogen treatment was effective in several studies in the EAE model of MS in mice(508−511) and downregulated pro-inflammatory cytokine production.(509) Therein, also treatment after disease onset was sufficient to reduce severity.(512) Tiwari-Woodruff et al.(476) observed differences of ERα and ERβ activation in EAE. ERα agonist treatment reduced severity of the disease from onset on, while ERβ agonist treatment had no effect in the early disease stage. At a later stage, ERβ activation caused a pronounced protective effect, however, as observed by faster recovery. ERβ knockout abolished this effect. ERα agonist treatment modulated cytokine levels toward an anti-inflammatory profile, suggesting a systemic immune-modulatory effect, whereas ERβ agonist treatment did not alter cytokine levels compared to vehicle. Both types of selective ER ligands reduced demyelination and axonal loss. Overall, these observations suggest beneficial effects of ER signaling for both subtypes(511,513) in neurodegeneration with a stronger anti-neuroinflammatory component for ERα and more pronounced neuroprotective activity for ERβ. The promising observations on estrogen actions in MS have also led to a number of clinical trials(514−517) to study estrogen treatment in female MS patients, which reported some beneficial effects but were not fully consistent. Circulating estrogen levels were found to inversely correlate with the number of active lesions and relapses. Estrogen treatment reduced the size of lesions and the annual number of relapses.

2.8.5. ER Ligands

Regarding medicinal chemistry, ERs are among the most well-studied NRs and the first NRs for which selective modulation has been broadly established with the selective estrogen receptor modulators (SERMs). Estrogens as the endogenous ER ligands are highly active on both isoforms and also have pharmacological relevance as drugs, but their use is limited by severe adverse effects including elevated risk for breast and endometrial cancer, thromboembolisms, and strokes.(518,519) The ligand binding domains of ERα and ERβ display only 59% sequence identity, which would suggest large differences. The ligand binding sites, however, differ in only two lipophilic residues (ERα: Leu384 and Met421 vs ERβ: Met336 and Ile373). In addition to these minor changes, differences in pocket shape and volume provide access to subtype preferential ligands. Advanced structural understanding of ERs and their modulation by ligands has been obtained from extensive cocrystal structure analysis and mechanistic studies,(520−523) which draw specific pharmacophore models and allow the design of subtype preferential modulators exhibiting agonism or antagonism on the ERs.(519) The two ER subtypes also differ in their expression patterns throughout the body which enables tissue selective ER modulation and can improve safety.(449,524) Because of their reduced systemic adverse effects, selective ERβ agonists might hold potential in neurodegenerative diseases. As outlined above, ERβ activation revealed protective effects in EAE models and against Aβ toxicity suggesting beneficial effects in MS and AD, respectively. However, both ERs are expressed in the CNS and are involved in anti-neuroinflammatory or anti-neurodegenerative effects. ERα activation exhibited stronger therapeutic effects in EAE, and several studies suggest different mechanisms for ERα- and ERβ-mediated effects in the CNS. ER subtype preferential ligands and SERMs might, therefore, not be sufficient to establish safe and effective ER modulators for therapeutic application in neurodegenerative diseases.
The large available collection of small molecule ER ligands comprises steroidal and nonsteroidal compounds and agonists, antagonists, and modulators (Scheme 11). The medicinal chemistry of ER ligands has been extensively summarized in several reviews.(519,525,526) The most active natural estrogen 17β-estradiol (96) and its derivative ethinylestradiol (100) as well as diethylstilbestrol (101) are widely used nonselective agonists for ERα and ERβ. Subtype preferential steroidal ER ligands were developed from estradiol by introduction of a γ-lactone over ring D (102, ERα preference) and a vinyl substituent in 8β-position (103, ERβ preference).(519) Medicinal chemistry efforts have also yielded several chemotypes of nonsteroidal subtype preferential ER agonists such as propylpyrazoletriol (97, PPT, ERα preference),(527) the rigid stilbene analogue 104 (ERα preference),(528) diarylpropionitrile (105, DPN, ERβ preference),(529) FERb033 (106, ERβ preference),(530) prinaberel and its descendant WAY200070 (107, ERβ preference),(531) and AC-186 (95, ERβ preference).(501) Activity in the CNS has been demonstrated for example for ERβ agonist DPN (105) in EAE(476) and for ERβ agonist AC-186 (95) in 6-OHDA-induced PD in rats,(501) suggesting them as preferable tools to further probe ERs in neurodegeneration. A key innovation in targeting ERs were the SERMs(532,533) tamoxifen (99), raloxifene (98),(527,534) bazedoxifene (108), and lasofoxifene (109),(535) which exhibit specific activity profiles on the ER subtypes in different tissues. Owing to the bulky residues added to the ER ligand pharmacophore, SERMs antagonize ER activity by preventing the binding of the activation function in helix H12 to the core of the ER LBD. In the resulting antagonist conformation, the ER LBD exhibits a different coregulator recruitment profile with a preference for corepressor binding.(532,533) Therein, ER modulation by SERMs varies in different tissues, which is rationalized by differential coregulator equipment of different cell types and tissues. They act as ER antagonists in breast tissue, as partial agonists in bone, and activity in endometrium varies depending on the SERM.(532,533) Brain penetration and activation of ER signaling in the CNS were recently demonstrated(536) for the SERM bazedoxifene (108), which could hence serve as an attractive tool to further probe ER modulation in neurodegeneration. Following the SERMs as ER modulatory drugs, the antiestrogen fulvestrant (110)(537) acting as a selective estrogen receptor degrader (SERD) has introduced another strategy to inhibit ER activity, and several further SERDs have been developed(533) of which elacestrant (111)(538) was found to cross the blood–brain barrier(539) suggesting it as a potential tool to study inhibition of ER signaling in the CNS.

Scheme 11

Scheme 11. ER Ligands

2.8.6. Conclusion

While evidence for a role of ER in PD is rather weak, the higher incidence of AD and MS in women and observations from multiple preclinical studies indicate a therapeutic potential of ER modulation in these neurodegenerative pathologies (summarized in Table 10). However, clinical trials have mostly failed to translate the beneficial effects from animal models to patients so far. Varying levels of circulating hormones in the patient cohorts might be an important factor for these failures and suggest that certain patient subgroups might benefit from ER modulation in neurodegeneration. The multitude of estrogen activities and potential adverse effects of ER activation must be considered as a potential limiting factor for ER agonist use in neurodegeneration. Selective targeting of ER in the brain might be an avenue to overcome such obstacles, but whether ER activation in the CNS is sufficient for the beneficial effects in neurodegeneration or whether peripheral effects are contributing remains elusive.
Table 10. Summarized Observations on ER in Neurodegeneration
ERα (= NR3A1; also known as ESR1) and ERβ (= NR3A2; also known as ESR2 and Erb)
ER in ADAD prevalence is higher in women than in men.(452)
ER activation protected against oxidative stress, excitotoxicity, and Aβ-mediated toxicity in cultured neurons(459,462,463) and in rodent models of neurotoxicity.(459,467−470)
ER activation decreased Aβ formation and promoted its clearance in vivo.(481−487)
Estrogen deficiency in the brain enhanced plaque formation in transgenic AD mice.(488)
ER in PDPD prevalence is higher in men than in women.(491)
No therapeutic benefit of ER activation in clinical trials(496,497)
ERβ activation counteracted loss of dopaminergic neurons, cognitive impairment, and motor deficits in 6-OHDA induced PD in rats.(501)
ER in MSMS prevalence is higher in women than in men.(453)
ER activation suppressed the inflammatory response of astrocytes in vitro(506) and in vivo.(507)
ER activation ameliorated EAE and downregulated pro-inflammatory cytokine release.(508−511)
ERα activation reduced EAE severity from onset on; ERβ activation improved recovery from EAE at a later stage.(476)
Clinical trials on ER activation in female MS patients reported some beneficial but inconsistent outcomes.(514−517)

3. Summary and Perspectives

ARTICLE SECTIONS
Jump To

The NR superfamily with its 48 ligand-activated transcription factors in human presents as a very attractive panel of potential therapeutic targets. Owing to the pronounced and durable effects that modulation of NRs exhibits on gene expression and hence on cellular phenotypes, it appears particularly suitable in the treatment of chronic diseases. Accordingly, NR ligands are used as drugs in cancer treatment (e.g., RXR, ER, androgen receptor), as potent anti-inflammatory agents (e.g., glucocorticoid receptor), and to counteract metabolic imbalance (e.g., PPAR, farnesoid X receptor). Neurodegenerative diseases such as AD, PD, and MS are chronic pathologies and closely linked to chronic inflammation or metabolic imbalance, suggesting a high potential of NR modulation in these diseases, too. Although early evidence for therapeutic effects of NR modulation in neurodegeneration dates back several decades, a major breakthrough has not been achieved, yet, and no NR ligand is used as a drug in such indications. However, preclinical research on NRs as therapeutic targets in neurodegeneration is constantly increasing, and cumulative evidence from pilot clinical trials and cohort studies on polymorphisms or altered NR expression in patients strongly supports the high potential of several NRs as future anti-neurodegenerative and anti-neuroinflammatory targets. The level of evidence for such therapeutic potential, naturally, varies for the different NRs, and most studies in the field have been performed for well-studied proteins such as PPAR and RXR. Nevertheless, recent findings particularly highlight also the orphan receptors Nurr1 and TLX, which are predominantly found in the brain as very promising targets for neurodegenerative disease treatment.
Despite very encouraging preclinical observations and evidence from human patients for the therapeutic potential of several NRs in neurodegeneration, pharmacological validation of these findings is often an obstacle and remains widely incomplete. This is mostly due to a lack of (custom) tool compounds with suitable properties to provide unambiguous data supporting observations from knockout studies or genetic overexpression. Especially the most promising targets such as the orphan receptors Nurr1 and TLX are poorly studied in terms of pharmacological control since potent modulators are not available. It is hence imperative to strengthen ligand discovery and tool compound development efforts for these NRs with the potentially greatest therapeutic promise in neurodegeneration. In addition, the mode-of-action or selectivity of several available tools that have already been used in preclinical models of neurodegeneration is questionable, especially for LXR, revERB, and NR4A receptors, which compromises the significance of studies based on these compounds. Achieving strong selectivity within the protein family may be challenging for some NR ligands, especially within NR families (such as NR4A) but is a key aspect for their proper applicability as pharmacological tools. For example, some evidence points to different roles of LXR subtypes and ER subtypes in the CNS, and recent observations suggest that the NR4A receptors Nur77 and Nurr1 may even have counteracting roles in neuroprotection and neurodegeneration. Such scenarios might also hold true for other closely related NRs, which highlights the importance of selectivity for tool compounds in this context. Some preclinical observations made with nonselective or poorly characterized tools hence cannot be clearly interpreted. Therefore, dedicated (custom) tool compounds to probe the potential of NRs in neurodegeneration are urgently required and must fulfill key criteria such as selectivity and clear mode-of-action but also sufficient BBB penetration.
Another open question often is the desired site/tissue of action for NR modulators to obtain therapeutic effects in neurodegeneration. The RXR agonist bexarotene (42), for example, exhibited some attractive therapeutic effects in vivo, but pharmacokinetic analysis demonstrated very limited CNS exposure suggesting involvement of systemic anti-inflammatory or metabolic effects. For certain widely expressed NRs (RXR, PPAR, LXR, VDR), specific brain targeting may hence not be necessary but should still be studied with suitable CNS penetrant tools to decipher systemic contributions and brain-directed effects of their therapeutic activities. In some cases (e.g., ER, PPAR, LXR), systemic effects might even be the dominant mode-of-action leading to improvements in neurodegenerative pathologies. Therein, adverse effects of systemic actions must also be considered when a long-term modulation of a NR is desired for anti-neurodegenerative activity. In contrast, less distributed NRs with a particularly high abundance in the brain (e.g., Nurr1) or even almost exclusive expression in the brain (e.g., TLX) will require ligands that are able to reach sufficient CNS concentrations which presents as an additional challenge to medicinal chemistry but has, for example, been achieved with dedicated brain-penetrant PPAR agonists. The dominant expression of these NRs in the brain on the other hand might be predictive of lower adverse effects upon their therapeutic modulation since systemic on-target effects are reduced. This may suggest potentially greater safety and hence a greater therapeutic potential for these orphan NRs as targets to treat neurodegeneration.
In summary, ligand-activated transcription factors present as highly attractive molecular targets to counteract neurodegenerative pathologies and thereby hold great promise to address high unmet medical needs in severe health burdens. Despite very promising findings for various nuclear receptors in preclinical models of neurodegeneration, we lack high-quality tool compounds to validate nuclear receptor modulation as a therapeutic strategy. Medicinal chemistry efforts must provide potent, selective, and brain-penetrant pharmacological tools especially for insufficiently studied orphan nuclear receptors to capture the full therapeutic potential of these proteins in neurodegeneration and beyond.

Author Information

ARTICLE SECTIONS
Jump To

  • Corresponding Author
  • Authors
    • Sabine Willems - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany
    • Daniel Zaienne - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany
  • Author Contributions

    S.W. and D.Z. contributed equally to this work.

  • Notes
    The authors declare no competing financial interest.

Biographies

ARTICLE SECTIONS
Jump To

Sabine Willems

Sabine Willems studied Pharmacy at Goethe University Frankfurt between 2012 and 2016 and received her license as a pharmacist in 2017. Currently, she is a Ph.D. student in Medicinal Chemistry at the Institute of Pharmaceutical Chemistry at the Goethe University focusing on the development and characterization of (orphan) nuclear receptor ligands.

Daniel Zaienne

Daniel Zaienne obtained Bachelor and Master of Science degrees in Chemistry from Goethe University Frankfurt in 2017 and in 2019, respectively. He then joined the Institute of Pharmaceutical Chemistry at Goethe University Frankfurt as a Ph.D. student, where he currently focuses on the synthesis and characterization of nuclear receptor ligands.

Daniel Merk

Daniel Merk graduated in Pharmaceutical Sciences and Pharmacy from LMU Munich in 2011 and obtained his Ph.D. in Pharmaceutical and Medicinal Chemistry from Goethe University Frankfurt in 2015. He was a Junior Group Leader in Pharmaceutical Chemistry at Goethe University Frankfurt and Postdoctoral ETH Fellowship Scholar at the Institute of Pharmaceutical Sciences of the Swiss Federal Institute of Technology (ETH) Zurich before he finished his Habilitation in Pharmaceutical Chemistry at Goethe University Frankfurt in 2019. Since then, he has been Independent Group Leader in Pharmaceutical Chemistry at Goethe University Frankfurt focusing on the Medicinal Chemistry and Pharmacology of nuclear receptors and their ligands. Recently, he joined LMU Munich as Chair of Pharmaceutical and Medicinal Chemistry.

Abbreviations
6-MP

6-mercaptopurine

6-OHDA

6-hydroxy dopamine

9-cis RA

9-cis retinoic acid

AADC

aromatic l-amino acid decarboxylase

ABC

ATP-binding cassette transporter

AD

Alzheimer’s disease

ADMET

absorption, distribution, metabolism, excretion, and toxicity

AF

activation function

APP

amyloid precursor protein

ATP

adenosine triphosphate

amyloid-β

Bcl-2

B-cell lymphoma 2

BBB

blood–brain barrier

BRET

bioluminescence resonance energy transfer

CD

circular dichroism

C-DIM

1,1-bis(3′-indolyl)-1-(p-substituted phenyl)-methane derivatives

CNS

central nervous system

CoREST

REST corepressor

COX

cyclooxygenase

CREB

cAMP response element binding protein

CSF

cerebrospinal fluid

DAT

dopamine transporter

DBD

DNA binding domain

DHA

docosahexaenoic acid

DR3/5

direct repeats spaced by 3/5 nucleotides

EAE

experimental autoimmune encephalomyelitis

EGFR

epidermal growth factor receptor

ER

estrogen receptor

fl

full length

GDNF

glial cell-derived neurotrophic factor

HTS

high-throughput screening

IFN

interferon

IL

interleukin

iNOS

inducible NO-synthase

IκBα

inhibitor of NF-κB

LBD

ligand binding domain

LPS

lipopolysaccharide

LXR

liver X receptor

MOG

myelin oligodendrocyte glycoprotein

MPP+

1-methyl-4-phenylpyridinium

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS

multiple sclerosis

NBRE

NGFI-B responsive element

NCoR

nuclear receptor corepressor

NFκB

nuclear factor-κB

NGFI-B

nerve growth factor-induced clone B

NMDA

N-methyl-d-aspartate

NOR-1

neuron derived orphan receptor 1

NR

nuclear receptor

NRE

nuclear receptor response element

NRIP

nuclear receptor-interacting protein

NSAIDs

nonsteroidal anti-inflammatory drugs

NSC

neural stem cell

Nurr1

nuclear receptor related-1 protein

NurRE

Nur response element

OL

oligodendrocyte

OPC

oligodendrocyte progenitor cells

PAINS

pan-assay interference compounds

PBMC

peripheral blood mononuclear cell

PD

Parkinson’s disease

PG

prostaglandin

P-gp

P-glycoprotein

PHA

phytohemagglutinin

PIASγ

protein inhibitor of activated STAT protein gamma

POMC

proopiomelanocortin

PPAR

peroxisome proliferator-activated receptor

PS1

presenilin 1

RE

response element

Ret

receptor tyrosine kinase Ret

RevERB

reverse ERB

RNAi

RNA interference

ROR

retinoic acid receptor related orphan receptors

RXR

retinoid X receptor

SAR

structure–activity relationship

SERM

selective estrogen receptor modulator

SMRT

silencing mediator for retinoid or thyroid hormone receptors

SNP

single-nucleotide polymorphism

SPR

surface plasmon resonance

TGF

transforming growth factor

Th

T helper cell

TH

tyrosine hydroxylase

THR

thyroid hormone receptor

TLX

tailless homologue

TNFα

tumor necrosis factor α

Treg

regulatory T cell

VDR

vitamin D receptor

VMAT2

vesicular monoamine transporter 2

References

ARTICLE SECTIONS
Jump To

This article references 539 other publications.

  1. 1
    Prince, M.; Bryce, R.; Albanese, E.; Wimo, A.; Ribeiro, W.; Ferri, C. P. The Global Prevalence of Dementia: A Systematic Review and Metaanalysis. Alzheimer's Dementia 2013, 9 (1), 6375.e2,  DOI: 10.1016/j.jalz.2012.11.007
  2. 2
    Moutinho, M.; Codocedo, J. F.; Puntambekar, S. S.; Landreth, G. E. Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation. Annu. Rev. Pharmacol. Toxicol. 2019, 59, 237261
  3. 3
    Abraha, I.; Rimland, J. M.; Trotta, F. M.; Dell’Aquila, G.; Cruz-Jentoft, A.; Petrovic, M.; Gudmundsson, A.; Soiza, R.; O’Mahony, D.; Guaita, A.; Cherubini, A. Systematic Review of Systematic Reviews of Non-Pharmacological Interventions to Treat Behavioural Disturbances in Older Patients with Dementia. The SENATOR-OnTop Series. BMJ. Open 2017, 7, e012759,  DOI: 10.1136/bmjopen-2016-012759
  4. 4
    Schmidt, R.; Hofer, E.; Bouwman, F. H.; Buerger, K.; Cordonnier, C.; Fladby, T.; Galimberti, D.; Georges, J.; Heneka, M. T.; Hort, J.; Laczó, J.; Molinuevo, J. L.; O’Brien, J. T.; Religa, D.; Scheltens, P.; Schott, J. M.; Sorbi, S. EFNS-ENS/EAN Guideline on Concomitant Use of Cholinesterase Inhibitors and Memantine in Moderate to Severe Alzheimer’s Disease. Eur. J. Neurol. 2015, 22 (6), 889898,  DOI: 10.1111/ene.12707
  5. 5
    McShane, R.; Areosa Sastre, A.; Minakaran, N. Memantine for Dementia. Cochrane Database Syst. Rev. 2006, No. 2. DOI: 10.1002/14651858.CD003154.pub5
  6. 6
    Birks, J.; Grimley Evans, J. Ginkgo Biloba for Cognitive Impairment and Dementia. Cochrane Database Syst. Rev. 2009, No. 1. DOI: 10.1002/14651858.CD003120.pub3
  7. 7
    Masters, C. L.; Bateman, R.; Blennow, K.; Rowe, C. C.; Sperling, R. A.; Cummings, J. L. Alzheimer’s Disease. Nat. Rev. Dis. Prim. 2015, 1 (1), 15056,  DOI: 10.1038/nrdp.2015.56
  8. 8
    Congdon, E. E.; Sigurdsson, E. M. Tau-Targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 2018, 14 (7), 399415,  DOI: 10.1038/s41582-018-0013-z
  9. 9
    Panza, F.; Lozupone, M.; Logroscino, G.; Imbimbo, B. P. A Critical Appraisal of Amyloid-β-Targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 2019, 15 (2), 7388,  DOI: 10.1038/s41582-018-0116-6
  10. 10
    Uliassi, E.; Gandini, A.; Perone, R. C.; Bolognesi, M. L. Neuroregeneration versus Neurodegeneration: Toward a Paradigm Shift in Alzheimer’s Disease Drug Discovery. Future Med. Chem. 2017, 9 (10), 9951013,  DOI: 10.4155/fmc-2017-0038
  11. 11
    Wang, J.; Gu, B. J.; Masters, C. L.; Wang, Y.-J. A Systemic View of Alzheimer Disease — Insights from Amyloid-β Metabolism beyond the Brain. Nat. Rev. Neurol. 2017, 13 (10), 612623,  DOI: 10.1038/nrneurol.2017.111
  12. 12
    Elkouzi, A.; Vedam-Mai, V.; Eisinger, R. S.; Okun, M. S. Emerging Therapies in Parkinson Disease — Repurposed Drugs and New Approaches. Nat. Rev. Neurol. 2019, 15 (4), 204223,  DOI: 10.1038/s41582-019-0155-7
  13. 13
    de Lau, L. M. L.; Breteler, M. M. B. Epidemiology of Parkinson’s Disease. Lancet Neurol. 2006, 5 (6), 525535,  DOI: 10.1016/S1474-4422(06)70471-9
  14. 14
    Parkinson’s Disease in Adults. NICE Guidelines, 2017, NG71.
  15. 15
    Deuschl, G.; de Bie, R. M. A. New Therapeutic Developments for Parkinson Disease. Nat. Rev. Neurol. 2019, 15 (2), 6869,  DOI: 10.1038/s41582-019-0133-0
  16. 16
    Doshi, A.; Chataway, J. Multiple Sclerosis, a Treatable Disease. Clin. Med. (Northfield. Il). 2016, 16 (6), s53s59,  DOI: 10.7861/clinmedicine.16-6-s53
  17. 17
    Tintore, M.; Vidal-Jordana, A.; Sastre-Garriga, J. Treatment of Multiple Sclerosis — Success from Bench to Bedside. Nat. Rev. Neurol. 2019, 15 (1), 5358,  DOI: 10.1038/s41582-018-0082-z
  18. 18
    Stangel, M.; Kuhlmann, T.; Matthews, P. M.; Kilpatrick, T. J. Achievements and Obstacles of Remyelinating Therapies in Multiple Sclerosis. Nat. Rev. Neurol. 2017, 13 (12), 742754,  DOI: 10.1038/nrneurol.2017.139
  19. 19
    Zhao, C.; Deng, W.; Gage, F. H. Mechanisms and Functional Implications of Adult Neurogenesis. Cell 2008, 132 (4), 645660,  DOI: 10.1016/j.cell.2008.01.033
  20. 20
    Germain, P.; Staels, B.; Dacquet, C.; Spedding, M.; Laudet, V. Overview of Nomenclature of Nuclear Receptors. Pharmacol. Rev. 2006, 58 (4), 685704,  DOI: 10.1124/pr.58.4.2
  21. 21
    Aranda, A.; Pascual, A. Nuclear Hormone Receptors and Gene Expression. Physiol. Rev. 2001, 81 (3), 12691304,  DOI: 10.1152/physrev.2001.81.3.1269
  22. 22
    De Bosscher, K.; Desmet, S. J.; Clarisse, D.; Estébanez-Perpiña, E.; Brunsveld, L. Nuclear Receptor Crosstalk — Defining the Mechanisms for Therapeutic Innovation. Nat. Rev. Endocrinol. 2020, 16 (7), 363377,  DOI: 10.1038/s41574-020-0349-5
  23. 23
    Evans, R. M.; Mangelsdorf, D. J. Nuclear Receptors, RXR, and the Big Bang. Cell 2014, 157, 255266,  DOI: 10.1016/j.cell.2014.03.012
  24. 24
    Rastinejad, F.; Huang, P.; Chandra, V.; Khorasanizadeh, S. Understanding Nuclear Receptor Form and Function Using Structural Biology. J. Mol. Endocrinol. 2013, 51 (3), T1T21,  DOI: 10.1530/JME-13-0173
  25. 25
    Negishi, M.; Kobayashi, K.; Sakuma, T.; Sueyoshi, T. Nuclear Receptor Phosphorylation in Xenobiotic Signal Transduction. J. Biol. Chem. 2020, 295 (45), 1521015225,  DOI: 10.1074/jbc.REV120.007933
  26. 26
    Rastinejad, F.; Ollendorff, V.; Polikarpov, I. Nuclear Receptor Full-Length Architectures: Confronting Myth and Illusion with High Resolution. Trends Biochem. Sci. 2015, 40 (1), 1624,  DOI: 10.1016/j.tibs.2014.10.011
  27. 27
    Weikum, E. R.; Liu, X.; Ortlund, E. A. The Nuclear Receptor Superfamily: A Structural Perspective. Protein Sci. 2018, 27, 18761892,  DOI: 10.1002/pro.3496
  28. 28
    Bain, D. L.; Heneghan, A. F.; Connaghan-Jones, K. D.; Miura, M. T. Nuclear Receptor Structure: Implications for Function. Annu. Rev. Physiol. 2007, 69 (1), 201220,  DOI: 10.1146/annurev.physiol.69.031905.160308
  29. 29
    Benoit, G.; Cooney, A.; Giguere, V.; Ingraham, H.; Lazar, M.; Muscat, G.; Perlmann, T.; Renaud, J.-P.; Schwabe, J.; Sladek, F.; Tsai, M.-J.; Laudet, V. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors. Pharmacol. Rev. 2006, 58 (4), 798836,  DOI: 10.1124/pr.58.4.10
  30. 30
    Robinson-Rechavi, M.; Garcia, H. E.; Laudet, V. The Nuclear Receptor Superfamily. J. Cell Sci. 2003, 116 (4), 585586,  DOI: 10.1242/jcs.00247
  31. 31
    Michalik, L.; Auwerx, J.; Berger, J. P.; Chatterjee, V. K.; Glass, C. K.; Gonzalez, F. J.; Grimaldi, P. A.; Kadowaki, T.; Lazar, M. A.; O’Rahilly, S.; Palmer, C. N. A.; Plutzky, J.; Reddy, J. K.; Spiegelman, B. M.; Staels, B.; Wahli, W. International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors. Pharmacol. Rev. 2006, 58 (4), 726741,  DOI: 10.1124/pr.58.4.5
  32. 32
    Warden, A.; Truitt, J.; Merriman, M.; Ponomareva, O.; Jameson, K.; Ferguson, L. B.; Mayfield, R. D.; Harris, R. A. Localization of PPAR Isotypes in the Adult Mouse and Human Brain. Sci. Rep. 2016, 6, 27681,  DOI: 10.1038/srep27618
  33. 33
    Gellrich, L.; Heitel, P.; Heering, J.; Kilu, W.; Pollinger, J.; Goebel, T.; Kahnt, A.; Arifi, S.; Pogoda, W.; Paulke, A.; Steinhilber, D.; Proschak, E.; Wurglics, M.; Schubert-Zsilavecz, M.; Chaikuad, A.; Knapp, S.; Bischoff, I.; Fürst, R.; Merk, D. L-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ. J. Med. Chem. 2020, 63 (13), 67276740,  DOI: 10.1021/acs.jmedchem.9b02150
  34. 34
    Proschak, E.; Heitel, P.; Kalinowsky, L.; Merk, D. Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery. J. Med. Chem. 2017, 60 (13), 52355266,  DOI: 10.1021/acs.jmedchem.6b01287
  35. 35
    Wahli, W.; Michalik, L. PPARs at the Crossroads of Lipid Signaling and Inflammation. Trends Endocrinol. Metab. 2012, 23, 351363,  DOI: 10.1016/j.tem.2012.05.001
  36. 36
    Lamers, C.; Schubert-Zsilavecz, M.; Merk, D. Therapeutic Modulators of Peroxisome Proliferator-Activated Receptors (PPAR): A Patent Review (2008–Present). Expert Opin. Ther. Pat. 2012, 22 (7), 803841,  DOI: 10.1517/13543776.2012.699042
  37. 37
    Lu, C.-H.; Yang, C.-Y.; Li, C.-Y.; Hsieh, C.; Ou, H.-T. Lower Risk of Dementia with Pioglitazone, Compared with Other Second-Line Treatments, in Metformin-Based Dual Therapy: A Population-Based Longitudinal Study. Diabetologia 2018, 61 (3), 562573,  DOI: 10.1007/s00125-017-4499-5
  38. 38
    Heneka, M. T.; Fink, A.; Doblhammer, G. Effect of Pioglitazone Medication on the Incidence of Dementia. Ann. Neurol. 2015, 78 (2), 284294,  DOI: 10.1002/ana.24439
  39. 39
    Chou, P.-S.; Ho, B.-L.; Yang, Y.-H. Effects of Pioglitazone on the Incidence of Dementia in Patients with Diabetes. J. Diabetes Complications 2017, 31 (6), 10531057,  DOI: 10.1016/j.jdiacomp.2017.01.006
  40. 40
    Kummer, M. P.; Heneka, M. T. PPARs in Alzheimer’s Disease. PPAR Res. 2008, 2008, 403896,  DOI: 10.1155/2008/403896
  41. 41
    Heneka, M. T.; Reyes-Irisarri, E.; Hull, M.; Kummer, M. P. Impact and Therapeutic Potential of PPARs in Alzheimers Disease. Curr. Neuropharmacol. 2011, 9 (4), 643650,  DOI: 10.2174/157015911798376325
  42. 42
    Du, J.; Zhang, L.; Liu, S.; Zhang, C.; Huang, X.; Li, J.; Zhao, N.; Wang, Z. PPARγ Transcriptionally Regulates the Expression of Insulin-Degrading Enzyme in Primary Neurons. Biochem. Biophys. Res. Commun. 2009, 383 (4), 485490,  DOI: 10.1016/j.bbrc.2009.04.047
  43. 43
    Quan, Q.; Qian, Y.; Li, X.; Li, M. Pioglitazone Reduces β Amyloid Levels via Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer’s Disease. Front. Aging Neurosci. 2019, 11, 178,  DOI: 10.3389/fnagi.2019.00178
  44. 44
    Sastre, M.; Dewachter, I.; Rossner, S.; Bogdanovic, N.; Rosen, E.; Borghgraef, P.; Evert, B. O.; Dumitrescu-Ozimek, L.; Thal, D. R.; Landreth, G.; Walter, J.; Klockgether, T.; Van Leuven, F.; Heneka, M. T. Nonsteroidal Anti-Inflammatory Drugs Repress β-Secretase Gene Promoter Activity by the Activation of PPARγ. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (2), 443448,  DOI: 10.1073/pnas.0503839103
  45. 45
    Sastre, M.; Dewachter, I.; Landreth, G. E.; Willson, T. M.; Klockgether, T.; Van Leuven, F.; Heneka, M. T. Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-γ Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of β-Secretase. J. Neurosci. 2003, 23 (30), 97969804,  DOI: 10.1523/JNEUROSCI.23-30-09796.2003
  46. 46
    Yang, S.; Chen, Z.; Cao, M.; Li, R.; Wang, Z.; Zhang, M. Pioglitazone Ameliorates Aβ42 Deposition in Rats with Diet-Induced Insulin Resistance Associated with AKT/GSK3β Activation. Mol. Med. Rep. 2017, 15 (5), 25882594,  DOI: 10.3892/mmr.2017.6342
  47. 47
    Chang, K. L.; Wong, L. R.; Pee, H. N.; Yang, S.; Ho, P. C. L. Reverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1Mice, a Model for Alzheimer’s Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist. Mol. Neurobiol. 2019, 56 (11), 72677283,  DOI: 10.1007/s12035-019-1586-2
  48. 48
    Yu, Y.; Li, X.; Blanchard, J.; Li, Y.; Iqbal, K.; Liu, F.; Gong, C.-X. Insulin Sensitizers Improve Learning and Attenuate Tau Hyperphosphorylation and Neuroinflammation in 3xTg-AD Mice. J. Neural Transm. 2015, 122 (4), 593606,  DOI: 10.1007/s00702-014-1294-z
  49. 49
    Du, J.; Sun, B.; Chen, K.; Fan, L.; Wang, Z. Antagonist of Peroxisome Proliferator-Activated Receptor γ Induces Cerebellar Amyloid-β Levels and Motor Dysfunction in APP/PS1 Transgenic Mice. Biochem. Biophys. Res. Commun. 2009, 384 (3), 357361,  DOI: 10.1016/j.bbrc.2009.04.148
  50. 50
    Fernandez-Martos, C. M.; Atkinson, R. A. K.; Chuah, M. I.; King, A. E.; Vickers, J. C. Combination Treatment with Leptin and Pioglitazone in a Mouse Model of Alzheimer’s Disease. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2017, 3 (1), 92106,  DOI: 10.1016/j.trci.2016.11.002
  51. 51
    Chen, J.; Li, S.; Sun, W.; Li, J. Anti-Diabetes Drug Pioglitazone Ameliorates Synaptic Defects in AD Transgenic Mice by Inhibiting Cyclin-Dependent Kinase5 Activity. PLoS One 2015, 10, e0123864  DOI: 10.1371/journal.pone.0123864
  52. 52
    Mandrekar-Colucci, S.; Karlo, J. C.; Landreth, G. E. Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer’s Disease. J. Neurosci. 2012, 32 (30), 1011710128,  DOI: 10.1523/JNEUROSCI.5268-11.2012
  53. 53
    Papadopoulos, P.; Rosa-Neto, P.; Rochford, J.; Hamel, E. Pioglitazone Improves Reversal Learning and Exerts Mixed Cerebrovascular Effects in a Mouse Model of Alzheimer’s Disease with Combined Amyloid-β and Cerebrovascular Pathology. PLoS One 2013, 8 (7), e68612,  DOI: 10.1371/journal.pone.0068612
  54. 54
    Prakash, A.; Kumar, A. Role of Nuclear Receptor on Regulation of BDNF and Neuroinflammation in Hippocampus of β-Amyloid Animal Model of Alzheimer’s Disease. Neurotoxic. Res. 2014, 25 (5), 335347,  DOI: 10.1007/s12640-013-9437-9
  55. 55
    Hamano, T.; Shirafuji, N.; Makino, C.; Yen, S.-H.; Kanaan, N. M.; Ueno, A.; Suzuki, J.; Ikawa, M.; Matsunaga, A.; Yamamura, O.; Kuriyama, M.; Nakamoto, Y. Pioglitazone Prevents Tau Oligomerization. Biochem. Biophys. Res. Commun. 2016, 478 (3), 10351042,  DOI: 10.1016/j.bbrc.2016.08.016
  56. 56
    Cho, D.-H.; Lee, E. J.; Kwon, K. J.; Shin, C. Y.; Song, K.-H.; Park, J.-H.; Jo, I.; Han, S.-H. Troglitazone, a Thiazolidinedione, Decreases Tau Phosphorylation through the Inhibition of Cyclin-Dependent Kinase 5 Activity in SH-SY5Y Neuroblastoma Cells and Primary Neurons. J. Neurochem. 2013, 126 (5), 685695,  DOI: 10.1111/jnc.12264
  57. 57
    Harrington, C.; Sawchak, S.; Chiang, C.; Davies, J.; Donovan, C.; Saunders, A. M.; Irizarry, M.; Jeter, B.; Zvartau-Hind, M.; H. van Dyck, C.; Gold, M. Rosiglitazone Does Not Improve Cognition or Global Function When Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies. Curr. Alzheimer Res. 2011, 8 (5), 592606,  DOI: 10.2174/156720511796391935
  58. 58
    Gold, M.; Alderton, C.; Zvartau-Hind, M.; Egginton, S.; Saunders, A. M.; Irizarry, M.; Craft, S.; Landreth, G.; Linnamägi, Ü.; Sawchak, S. Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study. Dementia Geriatr. Cognit. Disord. 2010, 30 (2), 131146,  DOI: 10.1159/000318845
  59. 59
    Cheng, H.; Shang, Y.; Jiang, L.; Shi, T.-L.; Wang, L. The Peroxisome Proliferators Activated Receptor-Gamma Agonists as Therapeutics for the Treatment of Alzheimer’s Disease and Mild-to-Moderate Alzheimer’s Disease: A Meta-Analysis. Int. J. Neurosci. 2016, 126 (4), 299307,  DOI: 10.3109/00207454.2015.1015722
  60. 60
    Liu, J.; Wang, L.; Jia, J. Peroxisome Proliferator-Activated Receptor-Gamma Agonists for Alzheimer’s Disease and Amnestic Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. Drugs Aging 2015, 32 (1), 5765,  DOI: 10.1007/s40266-014-0228-7
  61. 61
    Breidert, T.; Callebert, J.; Heneka, M. T.; Landreth, G.; Launay, J. M.; Hirsch, E. C. Protective Action of the Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone in a Mouse Model of Parkinson’s Disease. J. Neurochem. 2002, 82 (3), 615624,  DOI: 10.1046/j.1471-4159.2002.00990.x
  62. 62
    Quinn, L. P.; Crook, B.; Hows, M. E.; Vidgeon-Hart, M.; Chapman, H.; Upton, N.; Medhurst, A. D.; Virley, D. J. The PPARγ Agonist Pioglitazone Is Effective in the MPTP Mouse Model of Parkinson’s Disease through Inhibition of Monoamine Oxidase B. Br. J. Pharmacol. 2008, 154 (1), 226233,  DOI: 10.1038/bjp.2008.78
  63. 63
    Pisanu, A.; Lecca, D.; Mulas, G.; Wardas, J.; Simbula, G.; Spiga, S.; Carta, A. R. Dynamic Changes in Pro-and Anti-Inflammatory Cytokines in Microglia after PPAR-γ Agonist Neuroprotective Treatment in the MPTPp Mouse Model of Progressive Parkinson’s Disease. Neurobiol. Dis. 2014, 71, 280291,  DOI: 10.1016/j.nbd.2014.08.011
  64. 64
    Swanson, C. R.; Joers, V.; Bondarenko, V.; Brunner, K.; Simmons, H. A.; Ziegler, T. E.; Kemnitz, J. W.; Johnson, J. A.; Emborg, M. E. The PPAR-γ Agonist Pioglitazone Modulates Inflammation and Induces Neuroprotection in Parkinsonian Monkeys. J. Neuroinflammation 2011, 8, 91,  DOI: 10.1186/1742-2094-8-91
  65. 65
    Pinto, M.; Nissanka, N.; Peralta, S.; Brambilla, R.; Diaz, F.; Moraes, C. T. Pioglitazone Ameliorates the Phenotype of a Novel Parkinson’s Disease Mouse Model by Reducing Neuroinflammation. Mol. Neurodegener. 2016, 11, 25,  DOI: 10.1186/s13024-016-0090-7
  66. 66
    Lecca, D.; Nevin, D. K.; Mulas, G.; Casu, M. A.; Diana, A.; Rossi, D.; Sacchetti, G.; Carta, A. R. Neuroprotective and Anti-Inflammatory Properties of a Novel Non-Thiazolidinedione PPARγ Agonist in Vitro and in MPTP-Treated Mice. Neuroscience 2015, 302, 2335,  DOI: 10.1016/j.neuroscience.2015.04.026
  67. 67
    Lecca, D.; Janda, E.; Mulas, G.; Diana, A.; Martino, C.; Angius, F.; Spolitu, S.; Casu, M. A.; Simbula, G.; Boi, L.; Batetta, B.; Spiga, S.; Carta, A. R. Boosting Phagocytosis and Anti-Inflammatory Phenotype in Microglia Mediates Neuroprotection by PPARγ Agonist MDG548 in Parkinson’s Disease Models. Br. J. Pharmacol. 2018, 175 (16), 32983314,  DOI: 10.1111/bph.14214
  68. 68
    Swanson, C. R.; Du, E.; Johnson, D. A.; Johnson, J. A.; Emborg, M. E. Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR-γ Agonist against MPTP. PPAR Res. 2013, 2013, 582809  DOI: 10.1155/2013/582809
  69. 69
    Das, N. R.; Gangwal, R. P.; Damre, M. V.; Sangamwar, A. T.; Sharma, S. S. A PPAR-β/δ Agonist Is Neuroprotective and Decreases Cognitive Impairment in a Rodent Model of Parkinson’s Disease. Curr. Neurovasc. Res. 2014, 11 (2), 114124,  DOI: 10.2174/1567202611666140318114037
  70. 70
    Uppalapati, D.; Das, N. R.; Gangwal, R. P.; Damre, M. V.; Sangamwar, A. T.; Sharma, S. S. Neuroprotective Potential of Peroxisome Proliferator Activated Receptor-α Agonist in Cognitive Impairment in Parkinson’s Disease: Behavioral, Biochemical, and PBPK Profile. PPAR Res. 2014, 2014, 753587,  DOI: 10.1155/2014/753587
  71. 71
    Barbiero, J. K.; Santiago, R.; Tonin, F. S.; Boschen, S.; Da Silva, L. M.; De Paula Werner, M. F.; Da Cunha, C.; Lima, M. M. S.; Vital, M. A. B. F. PPAR-α Agonist Fenofibrate Protects against the Damaging Effects of MPTP in a Rat Model of Parkinson’s Disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2014, 53, 3544,  DOI: 10.1016/j.pnpbp.2014.02.009
  72. 72
    Martin, H. L.; Mounsey, R. B.; Sathe, K.; Mustafa, S.; Nelson, M. C.; Evans, R. M.; Teismann, P. A Peroxisome Proliferator-Activated Receptor-δ Agonist Provides Neuroprotection in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson’s Disease. Neuroscience 2013, 240, 191203,  DOI: 10.1016/j.neuroscience.2013.02.058
  73. 73
    Lee, Y.; Cho, J.-H.; Lee, S.; Lee, W.; Chang, S.-C.; Chung, H. Y.; Moon, H. R.; Lee, J. Neuroprotective Effects of MHY908, a PPAR α/γ Dual Agonist, in a MPTP-Induced Parkinson’s Disease Model. Brain Res. 2019, 1704, 4758,  DOI: 10.1016/j.brainres.2018.09.036
  74. 74
    Chen, L.; Xue, L.; Zheng, J.; Tian, X.; Zhang, Y.; Tong, Q. PPARß/δ Agonist Alleviates NLRP3 Inflammasome-Mediated Neuroinflammation in the MPTP Mouse Model of Parkinson’s Disease. Behav. Brain Res. 2019, 356, 483489,  DOI: 10.1016/j.bbr.2018.06.005
  75. 75
    Mounsey, R. B.; Martin, H. L.; Nelson, M. C.; Evans, R. M.; Teismann, P. The Effect of Neuronal Conditional Knock-out of Peroxisome Proliferator-Activated Receptors in the MPTP Mouse Model of Parkinson’s Disease. Neuroscience 2015, 300, 576584,  DOI: 10.1016/j.neuroscience.2015.05.048
  76. 76
    Tong, Q.; Wu, L.; Gao, Q.; Ou, Z.; Zhu, D.; Zhang, Y. PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α–Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson’s Disease. Mol. Neurobiol. 2016, 53 (8), 38223831,  DOI: 10.1007/s12035-015-9309-9
  77. 77
    Bonato, J. M.; Bassani, T. B.; Milani, H.; Vital, M. A. B. F.; de Oliveira, R. M. W. Pioglitazone Reduces Mortality, Prevents Depressive-like Behavior, and Impacts Hippocampal Neurogenesis in the 6-OHDA Model of Parkinson’s Disease in Rats. Exp. Neurol. 2018, 300, 188200,  DOI: 10.1016/j.expneurol.2017.11.009
  78. 78
    Machado, M. M. F.; Bassani, T. B.; Cóppola-Segovia, V.; Moura, E. L. R.; Zanata, S. M.; Andreatini, R.; Vital, M. A. B. F. PPAR-γ Agonist Pioglitazone Reduces Microglial Proliferation and NF-KB Activation in the Substantia Nigra in the 6-Hydroxydopamine Model of Parkinson’s Disease. Pharmacol. Rep. 2019, 71 (4), 556564,  DOI: 10.1016/j.pharep.2018.11.005
  79. 79
    Lee, E. Y.; Lee, J. E.; Park, J. H.; Shin, I. C.; Koh, H. C. Rosiglitazone, a PPAR-γ Agonist, Protects against Striatal Dopaminergic Neurodegeneration Induced by 6-OHDA Lesions in the Substantia Nigra of Rats. Toxicol. Lett. 2012, 213 (3), 332344,  DOI: 10.1016/j.toxlet.2012.07.016
  80. 80
    Martinez, A. A.; Morgese, M. G.; Pisanu, A.; Macheda, T.; Paquette, M. A.; Seillier, A.; Cassano, T.; Carta, A. R.; Giuffrida, A. Activation of PPAR Gamma Receptors Reduces Levodopa-Induced Dyskinesias in 6-OHDA-Lesioned Rats. Neurobiol. Dis. 2015, 74, 295304,  DOI: 10.1016/j.nbd.2014.11.024
  81. 81
    Gottschalk, C. G.; Roy, A.; Jana, M.; Kundu, M.; Pahan, K. Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons. Mol. Neurobiol. 2019, 56 (11), 78727887,  DOI: 10.1007/s12035-019-01649-y
  82. 82
    Brauer, R.; Bhaskaran, K.; Chaturvedi, N.; Dexter, D. T.; Smeeth, L.; Douglas, I. Glitazone Treatment and Incidence of Parkinson’s Disease among People with Diabetes: A Retrospective Cohort Study. PLoS Med. 2015, 12 (7), e1001854,  DOI: 10.1371/journal.pmed.1001854
  83. 83
    Mutez, E.; Duhamel, A.; Defebvre, L.; Bordet, R.; Destée, A.; Kreisler, A. Lipid-Lowering Drugs Are Associated with Delayed Onset and Slower Course of Parkinson’s Disease. Pharmacol. Res. 2009, 60 (1), 4145,  DOI: 10.1016/j.phrs.2009.03.010
  84. 84
    Szalardy, L.; Zadori, D.; Tanczos, E.; Simu, M.; Bencsik, K.; Vecsei, L.; Klivenyi, P. Elevated Levels of PPAR-Gamma in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Neurosci. Lett. 2013, 554, 131134,  DOI: 10.1016/j.neulet.2013.08.069
  85. 85
    Szalardy, L.; Zadori, D.; Bencsik, K.; Vecsei, L.; Klivenyi, P. Unlike PPARgamma, Neither Other PPARs nor PGC-1alpha Is Elevated in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Neurosci. Lett. 2017, 651, 128133,  DOI: 10.1016/j.neulet.2017.05.008
  86. 86
    Wouters, E.; Grajchen, E.; Jorissen, W.; Dierckx, T.; Wetzels, S.; Loix, M.; Tulleners, M. P.; Staels, B.; Stinissen, P.; Haidar, M.; Bogie, J. F. J.; Hendriks, J. J. A. Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis. Int. J. Mol. Sci. 2020, 21 (23), 9329,  DOI: 10.3390/ijms21239329
  87. 87
    Feinstein, D. L.; Galea, E.; Gavrilyuk, V.; Brosnan, C. F.; Whitacre, C. C.; Dumitrescu-Ozimek, L.; Landreth, G. E.; Pershadsingh, H. A.; Weinberg, G.; Heneka, M. T. Peroxisome Proliferator-Activated Receptor-γ Agonists Prevent Experimental Autoimmune Encephalomyelitis. Ann. Neurol. 2002, 51 (6), 694702,  DOI: 10.1002/ana.10206
  88. 88
    Klotz, L.; Burgdorf, S.; Dani, I.; Saijo, K.; Flossdorf, J.; Hucke, S.; Alferink, J.; Novak, N.; Beyer, M.; Mayer, G.; Langhans, B.; Klockgether, T.; Waisman, A.; Eberl, G.; Schultze, J.; Famulok, M.; Kolanus, W.; Glass, C.; Kurts, C.; Knolle, P. The Nuclear Receptor PPARγ Selectively Inhibits Th17 Differentiation in a T Cell–Intrinsic Fashion and Suppresses CNS Autoimmunity. J. Exp. Med. 2009, 206 (10), 20792089,  DOI: 10.1084/jem.20082771
  89. 89
    Chedrawe, M. A. J.; Holman, S. P.; Lamport, A.-C.; Akay, T.; Robertson, G. S. Pioglitazone Is Superior to Quetiapine, Clozapine and Tamoxifen at Alleviating Experimental Autoimmune Encephalomyelitis in Mice. J. Neuroimmunol. 2018, 321, 7282,  DOI: 10.1016/j.jneuroim.2018.06.001
  90. 90
    Diab, A.; Deng, C.; Smith, J. D.; Hussain, R. Z.; Phanavanh, B.; Lovett-Racke, A. E.; Drew, P. D.; Racke, M. K. Peroxisome Proliferator-Activated Receptor-γ Agonist 15-Deoxy-Δ12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis. J. Immunol. 2002, 168 (5), 25082515,  DOI: 10.4049/jimmunol.168.5.2508
  91. 91
    Diab, A.; Hussain, R. Z.; Lovett-Racke, A. E.; Chavis, J. A.; Drew, P. D.; Racke, M. K. Ligands for the Peroxisome Proliferator-Activated Receptor-γ and the Retinoid X Receptor Exert Additive Anti-Inflammatory Effects on Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2004, 148 (1–2), 116126,  DOI: 10.1016/j.jneuroim.2003.11.010
  92. 92
    Bernardo, A.; Giammarco, M. L.; De Nuccio, C.; Ajmone-Cat, M. A.; Visentin, S.; De Simone, R.; Minghetti, L. Docosahexaenoic Acid Promotes Oligodendrocyte Differentiation via PPAR-γ Signalling and Prevents Tumor Necrosis Factor-α-Dependent Maturational Arrest. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2017, 1862 (9), 10131023,  DOI: 10.1016/j.bbalip.2017.06.014
  93. 93
    De Nuccio, C.; Bernardo, A.; Cruciani, C.; De Simone, R.; Visentin, S.; Minghetti, L. Peroxisome Proliferator Activated Receptor-γ Agonists Protect Oligodendrocyte Progenitors against Tumor Necrosis Factor-Alpha-Induced Damage: Effects on Mitochondrial Functions and Differentiation. Exp. Neurol. 2015, 271, 506514,  DOI: 10.1016/j.expneurol.2015.07.014
  94. 94
    Storer, P. D.; Xu, J.; Chavis, J.; Drew, P. D. Peroxisome Proliferator-Activated Receptor-Gamma Agonists Inhibit the Activation of Microglia and Astrocytes: Implications for Multiple Sclerosis. J. Neuroimmunol. 2005, 161 (1–2), 113122,  DOI: 10.1016/j.jneuroim.2004.12.015
  95. 95
    Zhang, F.; Liu, F.; Yan, M.; Ji, H.; Hu, L.; Li, X.; Qian, J.; He, X.; Zhang, L.; Shen, A.; Cheng, C. Peroxisome Proliferator-Activated Receptor-γ Agonists Suppress INOS Expression Induced by LPS in Rat Primary Schwann Cells. J. Neuroimmunol. 2010, 218 (1–2), 3647,  DOI: 10.1016/j.jneuroim.2009.10.016
  96. 96
    Grajchen, E.; Wouters, E.; Van De Haterd, B.; Haidar, M.; Hardonnière, K.; Dierckx, T.; Van Broeckhoven, J.; Erens, C.; Hendrix, S.; Kerdine-Römer, S.; Hendriks, J. J. A.; Bogie, J. F. J. CD36-Mediated Uptake of Myelin Debris by Macrophages and Microglia Reduces Neuroinflammation. J. Neuroinflammation 2020, 17, 224,  DOI: 10.1186/s12974-020-01899-x
  97. 97
    Schmidt, S.; Moric, E.; Schmidt, M.; Sastre, M.; Feinstein, D. L.; Heneka, M. T. Anti-Inflammatory and Antiproliferative Actions of PPAR-γ Agonists on T Lymphocytes Derived from MS Patients. J. Leukocyte Biol. 2004, 75 (3), 478485,  DOI: 10.1189/jlb.0803402
  98. 98
    Polak, P. E.; Kalinin, S.; Dello Russo, C.; Gavrilyuk, V.; Sharp, A.; Peters, J. M.; Richardson, J.; Willson, T. M.; Weinberg, G.; Feinstein, D. L. Protective Effects of a Peroxisome Proliferator-Activated Receptor-β/δ Agonist in Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2005, 168 (1–2), 6575,  DOI: 10.1016/j.jneuroim.2005.07.006
  99. 99
    Kanakasabai, S.; Walline, C. C.; Chakraborty, S.; Bright, J. J. PPARδ Deficient Mice Develop Elevated Th1/Th17 Responses and Prolonged Experimental Autoimmune Encephalomyelitis. Brain Res. 2011, 1376, 101112,  DOI: 10.1016/j.brainres.2010.12.059
  100. 100
    Defaux, A.; Zurich, M. G.; Braissant, O.; Honegger, P.; Monnet-Tschudi, F. Effects of the PPAR-β Agonist GW501516 in an in Vitro Model of Brain Inflammation and Antibody-Induced Demyelination. J. Neuroinflammation 2009, 6, 15,  DOI: 10.1186/1742-2094-6-15
  101. 101
    Kanakasabai, S.; Chearwae, W.; Walline, C. C.; Iams, W.; Adams, S. M.; Bright, J. J. Peroxisome Proliferator-Activated Receptor δ Agonists Inhibit T Helper Type 1 (Th1) and Th17 Responses in Experimental Allergic Encephalomyelitis. Immunology 2010, 130 (4), 572588,  DOI: 10.1111/j.1365-2567.2010.03261.x
  102. 102
    Jana, M.; Mondal, S.; Gonzalez, F. J.; Pahan, K. Gemfibrozil, a Lipid-Lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-Activated Receptor-β. J. Biol. Chem. 2012, 287 (41), 3413434148,  DOI: 10.1074/jbc.M112.398552
  103. 103
    Sakuma, S.; Endo, T.; Kanda, T.; Nakamura, H.; Yamasaki, S.; Yamakawa, T. Synthesis of a Novel Human PPARδ Selective Agonist and Its Stimulatory Effect on Oligodendrocyte Differentiation. Bioorg. Med. Chem. Lett. 2011, 21 (1), 240244,  DOI: 10.1016/j.bmcl.2010.11.030
  104. 104
    Kaiser, C. C.; Shukla, D. K.; Stebbins, G. T.; Skias, D. D.; Jeffery, D. R.; Stefoski, D.; Katsamakis, G.; Feinstein, D. L. A Pilot Test of Pioglitazone as an Add-on in Patients with Relapsing Remitting Multiple Sclerosis. J. Neuroimmunol. 2009, 211 (1–2), 124130,  DOI: 10.1016/j.jneuroim.2009.04.011
  105. 105
    Shukla, D. K.; Kaiser, C. C.; Stebbins, G. T.; Feinstein, D. L. Effects of Pioglitazone on Diffusion Tensor Imaging Indices in Multiple Sclerosis Patients. Neurosci. Lett. 2010, 472 (3), 153156,  DOI: 10.1016/j.neulet.2010.01.046
  106. 106
    Negrotto, L.; Farez, M. F.; Correale, J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016, 73 (5), 520528,  DOI: 10.1001/jamaneurol.2015.4807
  107. 107
    Ratziu, V.; Harrison, S. A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S.; Drenth, J.; Anstee, Q. M.; Hum, D.; Hanf, R.; Roudot, A.; Megnien, S.; Staels, B.; Sanyal, A. Elafibranor, an Agonist of the Peroxisome Proliferator–Activated Receptor−α and – δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 2016, 150 (5), 11471159,  DOI: 10.1053/j.gastro.2016.01.038
  108. 108
    Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.; Cobb, J. E.; Collins, J. L.; Harrington, W. W.; Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-Miller, L. A.; Miller, J. F.; Mook, R. A.; Noble, S. A.; Oliver, W.; Parks, D. J.; Plunket, K. D.; Szewczyk, J. R.; Willson, T. M. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents. J. Med. Chem. 1998, 41 (25), 50205036,  DOI: 10.1021/jm9804127
  109. 109
    Cobb, J. E.; Blanchard, S. G.; Boswell, E. G.; Brown, K. K.; Charifson, P. S.; Cooper, J. P.; Collins, J. L.; Dezube, M.; Henke, B. R.; Hull-Ryde, E. A.; Lake, D. H.; Lenhard, J. M.; Oliver, W.; Oplinger, J.; Pentti, M.; Parks, D. J.; Plunket, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 3. Structure-Activity Relationship and Optimization of the N-Aryl Substituent. J. Med. Chem. 1998, 41 (25), 50555069,  DOI: 10.1021/jm980414r
  110. 110
    Collins, J. L.; Blanchard, S. G.; Boswell, G. E.; Charifson, P. S.; Cobb, J. E.; Henke, B. R.; Hull-Ryde, E. A.; Kazmierski, W. M.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J.; Lenhard, J. M.; Orband-Miller, L. A.; Gray-Nunez, Y.; Parks, D. J.; Plunkett, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety. J. Med. Chem. 1998, 41 (25), 50375054,  DOI: 10.1021/jm980413z
  111. 111
    Berger, J.; Leibowitz, M. D.; Doebber, T. W.; Elbrecht, A.; Zhang, B.; Zhou, G.; Biswas, C.; Cullinan, C. A.; Hayes, N. S.; Li, Y.; Tanen, M.; Ventre, J.; Wu, M. S.; Berger, G. D.; Mosley, R.; Marquis, R.; Santini, C.; Sahoo, S. P.; Tolman, R. L.; Smith, R. G.; M?ller, D. E. Novel Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects. J. Biol. Chem. 1999, 274 (10), 67186725,  DOI: 10.1074/jbc.274.10.6718
  112. 112
    Brown, P. J.; Stuart, L. W.; Hurley, K. P.; Lewis, M. C.; Winegar, D. A.; Wilson, J. G.; Wilkison, W. O.; Ittoop, O. R.; Willson, T. M. Identification of a Subtype Selective Human PPARα Agonist through Parallel-Array Synthesis. Bioorg. Med. Chem. Lett. 2001, 11 (9), 12251227,  DOI: 10.1016/S0960-894X(01)00188-3
  113. 113
    Kane, C. D.; Stevens, K. A.; Fischer, J. E.; Haghpassand, M.; Royer, L. J.; Aldinger, C.; Landschulz, K. T.; Zagouras, P.; Bagley, S. W.; Hada, W.; Dullea, R.; Hayward, C. M.; Francone, O. L. Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor α Agonists with Robust Hypolipidemic Activity in Vivo. Mol. Pharmacol. 2009, 75 (2), 296306,  DOI: 10.1124/mol.108.051656
  114. 114
    Kuwabara, K.; Murakami, K.; Todo, M.; Aoki, T.; Asaki, T.; Murai, M.; Yano, J. A Novel Selective Peroxisome Proliferator-Activated Receptor α Agonist, 2-Methyl-c-5-[4-[5-Methyl-2-(4-Methylphenyl)-4-Oxazolyl]Butyl]-1, 3-Dioxane-r-2-Carboxylic Acid (NS-220), Potently Decreases Plasma Triglyceride and Glucose Levels and Modifies Lipopr. J. Pharmacol. Exp. Ther. 2004, 309 (3), 970977,  DOI: 10.1124/jpet.103.064659
  115. 115
    Santilli, A. A.; Scotese, A. C.; Tomarelli, R. M. A Potent Antihypercholesterolemic Agent: [4-Chloro-6-(2,3-Xylidino)-2-Pyrimidinylthio]Acetic Acid (Wy-14643). Experientia 1974, 30 (10), 11101111,  DOI: 10.1007/BF01923636
  116. 116
    Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: From Orphan Receptors to Drug Discovery. J. Med. Chem. 2000, 43, 527550,  DOI: 10.1021/jm990554g
  117. 117
    Pollinger, J.; Gellrich, L.; Schierle, S.; Kilu, W.; Schmidt, J.; Kalinowsky, L.; Ohrndorf, J.; Kaiser, A.; Heering, J.; Proschak, E.; Merk, D. Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation. J. Med. Chem. 2019, 62 (4), 21122126,  DOI: 10.1021/acs.jmedchem.8b01848
  118. 118
    Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.; Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.; Kliewer, S. A.; Lehmann, J. M. The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor γ Agonism and the Antihyperglycemic Activity of Thiazolidinediones. J. Med. Chem. 1996, 39 (3), 665668,  DOI: 10.1021/jm950395a
  119. 119
    Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ). J. Biol. Chem. 1995, 270 (22), 1295312956,  DOI: 10.1074/jbc.270.22.12953
  120. 120
    Brown, K. K.; Henke, B. R.; Blanchard, S. G.; Cobb, J. E.; Mook, R.; Kaldor, I.; Kliewer, S. A.; Lehmann, J. M.; Lenhard, J. M.; Harrington, W. W.; Novak, P. J.; Faison, W.; Binz, J. G.; Hashim, M. A.; Oliver, W. O.; Brown, H. R.; Parks, D. J.; Plunket, K. D.; Tong, W. Q.; Menius, J. A.; Adkison, K.; Noble, S. A.; Willson, T. M. A Novel N-Aryl Tyrosine Activator of Peroxisome Proliferator-Activated Receptor-γ Reverses the Diabetic Phenotype of the Zucker Diabetic Fatty Rat. Diabetes 1999, 48 (7), 14151424,  DOI: 10.2337/diabetes.48.7.1415
  121. 121
    Hanke, T.; Cheung, S.-Y.; Kilu, W.; Heering, J.; Ni, X.; Planz, V.; Schierle, S.; Faudone, G.; Friedrich, M.; Wanior, M.; Werz, O.; Windbergs, M.; Proschak, E.; Schubert-Zsilavecz, M.; Chaikuad, A.; Knapp, S.; Merk, D. A Selective Modulator of Peroxisome Proliferator-Activated Receptor γ with an Unprecedented Binding Mode. J. Med. Chem. 2020, 63 (9), 45554561,  DOI: 10.1021/acs.jmedchem.9b01786
  122. 122
    Leesnitzer, L. M.; Parks, D. J.; Bledsoe, R. K.; Cobb, J. E.; Collins, J. L.; Consler, T. G.; Davis, R. G.; Hull-Ryde, E. A.; Lenhard, J. M.; Patel, L.; Plunket, K. D.; Shenk, J. L.; Stimmel, J. B.; Therapontos, C.; Willson, T. M.; Blanchard, S. G. Functional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662. Biochemistry 2002, 41 (21), 66406650,  DOI: 10.1021/bi0159581
  123. 123
    Oliver, W. R.; Shenk, J. L.; Snaith, M. R.; Russell, C. S.; Plunket, K. D.; Bodkin, N. L.; Lewis, M. C.; Winegar, D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu, H. E.; Sternbach, D. D.; Kliewer, S. A.; Hansen, B. C.; Willson, T. M. A Selective Peroxisome Proliferator-Activated Receptor δ Agonist Promotes Reverse Cholesterol Transport. Proc. Natl. Acad. Sci. U. S. A. 2001, 98 (9), 53065311,  DOI: 10.1073/pnas.091021198
  124. 124
    Sznaidman, M. L.; Haffner, C. D.; Maloney, P. R.; Fivush, A.; Chao, E.; Goreham, D.; Sierra, M. L.; LeGrumelec, C.; Xu, H. E.; Montana, V. G.; Lambert, M. H.; Willson, T. M.; Oliver, W. R.; Sternbach, D. D. Novel Selective Small Molecule Agonists for Peroxisome Proliferator-Activated Receptor δ (PPARδ) - Synthesis and Biological Activity. Bioorg. Med. Chem. Lett. 2003, 13 (9), 15171521,  DOI: 10.1016/S0960-894X(03)00207-5
  125. 125
    Zhang, R.; Wang, A.; DeAngelis, A.; Pelton, P.; Xu, J.; Zhu, P.; Zhou, L.; Demarest, K.; Murray, W. V.; Kuo, G.-H. Discovery of Para-Alkylthiophenoxyacetic Acids as a Novel Series of Potent and Selective PPARδ Agonists. Bioorg. Med. Chem. Lett. 2007, 17 (14), 38553859,  DOI: 10.1016/j.bmcl.2007.05.007
  126. 126
    Chang, K. L.; Pee, H. N.; Yang, S.; Ho, P. C. Influence of Drug Transporters and Stereoselectivity on the Brain Penetration of Pioglitazone as a Potential Medicine against Alzheimer’s Disease. Sci. Rep. 2015, 5, 9000,  DOI: 10.1038/srep09000
  127. 127
    Sime, M.; Allan, A. C.; Chapman, P.; Fieldhouse, C.; Giblin, G. M. P.; Healy, M. P.; Lambert, M. H.; Leesnitzer, L. M.; Lewis, A.; Merrihew, R. V.; Rutter, R. A.; Sasse, R.; Shearer, B. G.; Willson, T. M.; Xu, R. X.; Virley, D. J. Discovery of GSK1997132B a Novel Centrally Penetrant Benzimidazole PPARγ Partial Agonist. Bioorg. Med. Chem. Lett. 2011, 21 (18), 55685572,  DOI: 10.1016/j.bmcl.2011.06.088
  128. 128
    Uriz-Huarte, A.; Date, A.; Ang, H.; Ali, S.; Brady, H. J. M.; Fuchter, M. J. The Transcriptional Repressor REV-ERB as a Novel Target for Disease. Bioorg. Med. Chem. Lett. 2020, 30 (17), 127395,  DOI: 10.1016/j.bmcl.2020.127395
  129. 129
    Kojetin, D. J.; Burris, T. P. REV-ERB and ROR Nuclear Receptors as Drug Targets. Nat. Rev. Drug Discovery 2014, 13 (3), 197216,  DOI: 10.1038/nrd4100
  130. 130
    Chang, C.; Loo, C.-S.; Zhao, X.; Solt, L. A.; Liang, Y.; Bapat, S. P.; Cho, H.; Kamenecka, T. M.; Leblanc, M.; Atkins, A. R.; Yu, R. T.; Downes, M.; Burris, T. P.; Evans, R. M.; Zheng, Y. The Nuclear Receptor REV-ERBα Modulates Th17 Cell-Mediated Autoimmune Disease. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (37), 1852818536,  DOI: 10.1073/pnas.1907563116
  131. 131
    Lazar, M. A.; Hodin, R. A.; Darling, D. S.; Chin, W. W. A Novel Member of the Thyroid/Steroid Hormone Receptor Family Is Encoded by the Opposite Strand of the Rat c-ErbA Alpha Transcriptional Unit. Mol. Cell. Biol. 1989, 9 (3), 11281136,  DOI: 10.1128/MCB.9.3.1128
  132. 132
    Forman, B. M.; Chen, J.; Blumberg, B.; Kliewer, S. A.; Henshaw, R.; Ong, E. S.; Evans, R. M. Cross-Talk among ROR Alpha 1 and the Rev-Erb Family of Orphan Nuclear Receptors. Mol. Endocrinol. 1994, 8 (9), 12531261,  DOI: 10.1210/mend.8.9.7838158
  133. 133
    Dumas, B.; Harding, H. P.; Choi, H. S.; Lehmann, K. A.; Chung, M.; Lazar, M. A.; Moore, D. D. A New Orphan Member of the Nuclear Hormone Receptor Superfamily Closely Related to Rev-Erb. Mol. Endocrinol. 1994, 8 (8), 9961005,  DOI: 10.1210/mend.8.8.7997240
  134. 134
    Yin, L.; Lazar, M. A. The Orphan Nuclear Receptor Rev-Erbα Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene. Mol. Endocrinol. 2005, 19 (6), 14521459,  DOI: 10.1210/me.2005-0057
  135. 135
    Torra, I. P.; Tsibulsky, V.; Delaunay, F.; Saladin, R.; Laudet, V.; Fruchart, J.-C.; Kosykh, V.; Staels, B. Circadian and Glucocorticoid Regulation of Rev-Erbα Expression in Liver. Endocrinology 2000, 141 (10), 37993806,  DOI: 10.1210/endo.141.10.7708
  136. 136
    Balsalobre, A.; Damiola, F.; Schibler, U. A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells. Cell 1998, 93 (6), 929937,  DOI: 10.1016/S0092-8674(00)81199-X
  137. 137
    Wolff, S. E. C.; Wang, X.-L.; Jiao, H.; Sun, J.; Kalsbeek, A.; Yi, C.-X.; Gao, Y. The Effect of Rev-Erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia. Front. Immunol. 2020, 11, 550145,  DOI: 10.3389/fimmu.2020.550145
  138. 138
    Guo, D.; Zhu, Y.; Sun, H.; Xu, X.; Zhang, S.; Hao, Z.; Wang, G.; Mu, C.; Ren, H. Pharmacological Activation of REV-ERBα Represses LPS-Induced Microglial Activation through the NF-KB Pathway. Acta Pharmacol. Sin. 2019, 40 (1), 2634,  DOI: 10.1038/s41401-018-0064-0
  139. 139
    Roby, D. A.; Ruiz, F.; Kermath, B. A.; Voorhees, J. R.; Niehoff, M.; Zhang, J.; Morley, J. E.; Musiek, E. S.; Farr, S. A.; Burris, T. P. Pharmacological Activation of the Nuclear Receptor REV-ERB Reverses Cognitive Deficits and Reduces Amyloid-β Burden in a Mouse Model of Alzheimer’s Disease. PLoS One 2019, 14 (4), e0215004,  DOI: 10.1371/journal.pone.0215004
  140. 140
    Griffin, P.; Dimitry, J. M.; Sheehan, P. W.; Lananna, B. V.; Guo, C.; Robinette, M. L.; Hayes, M. E.; Cedeño, M. R.; Nadarajah, C. J.; Ezerskiy, L. A.; Colonna, M.; Zhang, J.; Bauer, A. Q.; Burris, T. P.; Musiek, E. S. Circadian Clock Protein Rev-Erbα Regulates Neuroinflammation. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (11), 51025107,  DOI: 10.1073/pnas.1812405116
  141. 141
    Lee, J.; Kim, D. E.; Griffin, P.; Sheehan, P. W.; Kim, D.-H.; Musiek, E. S.; Yoon, S.-Y. Inhibition of REV-ERBs Stimulates Microglial Amyloid-Beta Clearance and Reduces Amyloid Plaque Deposition in the 5XFAD Mouse Model of Alzheimer’s Disease. Aging Cell 2020, 19 (2), e13078,  DOI: 10.1111/acel.13078
  142. 142
    Raghuram, S.; Stayrook, K. R.; Huang, P.; Rogers, P. M.; Nosie, A. K.; McClure, D. B.; Burris, L. L.; Khorasanizadeh, S.; Burris, T. P.; Rastinejad, F. Identification of Heme as the Ligand for the Orphan Nuclear Receptors REV-ERBα and REV-ERBβ. Nat. Struct. Mol. Biol. 2007, 14 (12), 12071213,  DOI: 10.1038/nsmb1344
  143. 143
    Trump, R. P.; Bresciani, S.; Cooper, A. W. J.; Tellam, J. P.; Wojno, J.; Blaikley, J.; Orband-Miller, L. A.; Kashatus, J. A.; Boudjelal, M.; Dawson, H. C.; Loudon, A.; Ray, D.; Grant, D.; Farrow, S. N.; Willson, T. M.; Tomkinson, N. C. O. Optimized Chemical Probes for REV-ERBα. J. Med. Chem. 2013, 56 (11), 47294737,  DOI: 10.1021/jm400458q
  144. 144
    Noel, R.; Song, X.; Shin, Y.; Banerjee, S.; Kojetin, D.; Lin, L.; Ruiz, C. H.; Cameron, M. D.; Burris, T. P.; Kamenecka, T. M. Synthesis and SAR of Tetrahydroisoquinolines as Rev-Erbα Agonists. Bioorg. Med. Chem. Lett. 2012, 22 (11), 37393742,  DOI: 10.1016/j.bmcl.2012.04.023
  145. 145
    Westermaier, Y.; Ruiz-Carmona, S.; Theret, I.; Perron-Sierra, F.; Poissonnet, G.; Dacquet, C.; Boutin, J. A.; Ducrot, P.; Barril, X. Binding Mode Prediction and MD/MMPBSA-Based Free Energy Ranking for Agonists of REV-ERBα/NCoR. J. Comput.-Aided Mol. Des. 2017, 31 (8), 755775,  DOI: 10.1007/s10822-017-0040-7
  146. 146
    Kojetin, D.; Wang, Y.; Kamenecka, T. M.; Burris, T. P. Identification of SR8278, a Synthetic Antagonist of the Nuclear Heme Receptor REV-ERB. ACS Chem. Biol. 2011, 6 (2), 131134,  DOI: 10.1021/cb1002575
  147. 147
    De Mei, C; Ercolani, L; Parodi, C; Veronesi, M; Vecchio, C L.; Bottegoni, G; Torrente, E; Scarpelli, R; Marotta, R; Ruffili, R; Mattioli, M; Reggiani, A; Wade, M; Grimaldi, B Dual Inhibition of REV-ERBβ and Autophagy as a Novel Pharmacological Approach to Induce Cytotoxicity in Cancer Cells. Oncogene 2015, 34 (20), 25972608,  DOI: 10.1038/onc.2014.203
  148. 148
    Torrente, E.; Parodi, C.; Ercolani, L.; De Mei, C.; Ferrari, A.; Scarpelli, R.; Grimaldi, B. Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy. J. Med. Chem. 2015, 58 (15), 59005915,  DOI: 10.1021/acs.jmedchem.5b00511
  149. 149
    Dierickx, P.; Emmett, M. J.; Jiang, C.; Uehara, K.; Liu, M.; Adlanmerini, M.; Lazar, M. A. SR9009 Has REV-ERB–Independent Effects on Cell Proliferation and Metabolism. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (25), 1214712152,  DOI: 10.1073/pnas.1904226116
  150. 150
    Moore, D. D.; Kato, S.; Xie, W.; Mangelsdorf, D. J.; Schmidt, D. R.; Xiao, R.; Kliewer, S. A. International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor. Pharmacol. Rev. 2006, 58 (4), 742759,  DOI: 10.1124/pr.58.4.6
  151. 151
    Viennois, E.; Mouzat, K.; Dufour, J.; Morel, L.; Lobaccaro, J.-M.; Baron, S. Selective Liver X Receptor Modulators (SLiMs): What Use in Human Health?. Mol. Cell. Endocrinol. 2012, 351 (2), 129141,  DOI: 10.1016/j.mce.2011.08.036
  152. 152
    Mouzat, K.; Chudinova, A.; Polge, A.; Kantar, J.; Camu, W.; Raoul, C.; Lumbroso, S. Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?. Int. J. Mol. Sci. 2019, 20 (16), 3858,  DOI: 10.3390/ijms20163858
  153. 153
    Hong, C.; Tontonoz, P. Liver X Receptors in Lipid Metabolism: Opportunities for Drug Discovery. Nature Reviews Drug Discovery 2014, 13, 433444,  DOI: 10.1038/nrd4280
  154. 154
    Sodhi, R. K.; Singh, N. Liver X Receptors: Emerging Therapeutic Targets for Alzheimer’s Disease. Pharmacol Res. 2013, 72, 4551,  DOI: 10.1016/j.phrs.2013.03.008
  155. 155
    Moutinho, M.; Landreth, G. E. Therapeutic Potential of Nuclear Receptor Agonists in Alzheimer’s Disease. J. Lipid Res. 2017, 58 (10), 19371949,  DOI: 10.1194/jlr.R075556
  156. 156
    Björkhem, I.; Meaney, S. Brain Cholesterol: Long Secret Life behind a Barrier. Arterioscler., Thromb., Vasc. Biol. 2004, 24 (5), 806815,  DOI: 10.1161/01.ATV.0000120374.59826.1b
  157. 157
    Hussain, G.; Wang, J.; Rasul, A.; Anwar, H.; Imran, A.; Qasim, M.; Zafar, S.; Kamran, S. K. S.; Razzaq, A.; Aziz, N.; Ahmad, W.; Shabbir, A.; Iqbal, J.; Baig, S. M.; Sun, T. Role of Cholesterol and Sphingolipids in Brain Development and Neurological Diseases. Lipids in Health and Disease 2019, 18, 26,  DOI: 10.1186/s12944-019-0965-z
  158. 158
    Mauch, D. H.; Nägler, K.; Schumacher, S.; Göritz, C.; Müller, E.-C.; Otto, A.; Pfrieger, F. W. CNS Synaptogenesis Promoted by Glia-Derived Cholesterol. Science 2001, 294 (5545), 13541357,  DOI: 10.1126/science.294.5545.1354
  159. 159
    Zhang, J.; Liu, Q. Cholesterol Metabolism and Homeostasis in the Brain. Protein Cell 2015, 6 (4), 254264,  DOI: 10.1007/s13238-014-0131-3
  160. 160
    Abildayeva, K.; Jansen, P. J.; Hirsch-Reinshagen, V.; Bloks, V. W.; Bakker, A. H. F.; Ramaekers, F. C. S.; De Vente, J.; Groen, A. K.; Wellington, C. L.; Kuipers, F.; Mulder, M. 24(S)-Hydroxycholesterol Participates in a Liver X Receptor-Controlled Pathway in Astrocytes That Regulates Apolipoprotein E-Mediated Cholesterol Efflux. J. Biol. Chem. 2006, 281 (18), 1279912808,  DOI: 10.1074/jbc.M601019200
  161. 161
    Peet, D. J.; Turley, S. D.; Ma, W.; Janowski, B. A.; Lobaccaro, J. M. A.; Hammer, R. E.; Mangelsdorf, D. J. Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα. Cell 1998, 93 (5), 693704,  DOI: 10.1016/S0092-8674(00)81432-4
  162. 162
    Andersson, S.; Gustafsson, N.; Warner, M.; Gustafsson, J.-Å. Inactivation of Liver X Receptor β Leads to Adult-Onset Motor Neuron Degeneration in Male Mice. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (10), 38573862,  DOI: 10.1073/pnas.0500634102
  163. 163
    Bigini, P.; Steffensen, K. R.; Ferrario, A.; Diomede, L.; Ferrara, G.; Barbera, S.; Salzano, S.; Fumagalli, E.; Ghezzi, P.; Mennini, T.; Gustafsson, J.-Å. Neuropathologic and Biochemical Changes During Disease Progression in Liver X Receptor β –/– Mice, A Model of Adult Neuron Disease. J. Neuropathol. Exp. Neurol. 2010, 69 (6), 593605,  DOI: 10.1097/NEN.0b013e3181df20e1
  164. 164
    Meffre, D.; Shackleford, G.; Hichor, M.; Gorgievski, V.; Tzavara, E. T.; Trousson, A.; Ghoumari, A. M.; Deboux, C.; Oumesmar, B. N.; Liere, P.; Schumacher, M.; Baulieu, E.-E.; Charbonnier, F.; Grenier, J.; Massaad, C. Liver X Receptors Alpha and Beta Promote Myelination and Remyelination in the Cerebellum. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (24), 75877592,  DOI: 10.1073/pnas.1424951112
  165. 165
    Song, X.-Y.; Wu, W.-F.; Gabbi, C.; Dai, Y.-B.; So, M.; Chaurasiya, S. P.; Wang, L.; Warner, M.; Gustafsson, J. Å. Retinal and Optic Nerve Degeneration in Liver X Receptor β Knockout Mice. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (33), 1650716512,  DOI: 10.1073/pnas.1904719116
  166. 166
    Zelcer, N.; Khanlou, N.; Clare, R.; Jiang, Q.; Reed-Geaghan, E. G.; Landreth, G. E.; Vinters, H. V.; Tontonoz, P. Attenuation of Neuroinflammation and Alzheimer’s Disease Pathology by Liver x Receptors. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (25), 1060110606,  DOI: 10.1073/pnas.0701096104
  167. 167
    Cui, W.; Sun, Y.; Wang, Z.; Xu, C.; Peng, Y.; Li, R. Liver X Receptor Activation Attenuates Inflammatory Response and Protects Cholinergic Neurons in APP/PS1 Transgenic Mice. Neuroscience 2012, 210, 200210,  DOI: 10.1016/j.neuroscience.2012.02.047
  168. 168
    Strittmatter, W. J.; Saunders, A. M.; Schmechel, D.; Pericak-Vance, M.; Enghild, J.; Salvesen, G. S.; Roses, A. D. Apolipoprotein E: High-Avidity Binding to β-Amyloid and Increased Frequency of Type 4 Allele in Late-Onset Familial Alzheimer Disease. Proc. Natl. Acad. Sci. U. S. A. 1993, 90 (5), 19771981,  DOI: 10.1073/pnas.90.5.1977
  169. 169
    Pitas, R. E.; Boyles, J. K.; Lee, S. H.; Foss, D.; Mahley, R. W. Astrocytes Synthesize Apolipoprotein E and Metabolize Apolipoprotein E-Containing Lipoproteins. Biochim. Biophys. Acta, Lipids Lipid Metab. 1987, 917 (1), 148161,  DOI: 10.1016/0005-2760(87)90295-5
  170. 170
    Ignatius, M. J.; Gebicke-Harter, P. J.; Skene, J. H.; Schilling, J. W.; Weisgraber, K. H.; Mahley, R. W.; Shooter, E. M. Expression of Apolipoprotein E during Nerve Degeneration and Regeneration. Proc. Natl. Acad. Sci. U. S. A. 1986, 83 (4), 11251129,  DOI: 10.1073/pnas.83.4.1125
  171. 171
    Fukumoto, H.; Deng, A.; Irizarry, M. C.; Fitzgerald, M. L.; Rebeck, G. W. Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Aβ Levels. J. Biol. Chem. 2002, 277 (50), 4850848513,  DOI: 10.1074/jbc.M209085200
  172. 172
    Sun, Y.; Yao, J.; Kim, T.-W.; Tall, A. R. Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide Secretion. J. Biol. Chem. 2003, 278 (30), 2768827694,  DOI: 10.1074/jbc.M300760200
  173. 173
    Koldamova, R. P.; Lefterov, I. M.; Staufenbiel, M.; Wolfe, D.; Huang, S.; Glorioso, J. C.; Walter, M.; Roth, M. G.; Lazo, J. S. The Liver X Receptor Ligand T0901317 Decreases Amyloid β Production in Vitro and in a Mouse Model of Alzheimer’s Disease. J. Biol. Chem. 2005, 280 (6), 40794088,  DOI: 10.1074/jbc.M411420200
  174. 174
    Fitz, N. F.; Cronican, A.; Pham, T.; Fogg, A.; Fauq, A. H.; Chapman, R.; Lefterov, I.; Koldamova, R. Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice. J. Neurosci. 2010, 30 (20), 68626872,  DOI: 10.1523/JNEUROSCI.1051-10.2010
  175. 175
    Cui, W.; Sun, Y.; Wang, Z.; Xu, C.; Xu, L.; Wang, F.; Chen, Z.; Peng, Y.; Li, R. Activation of Liver x Receptor Decreases BACE1 Expression and Activity by Reducing Membrane Cholesterol Levels. Neurochem. Res. 2011, 36 (10), 19101921,  DOI: 10.1007/s11064-011-0513-3
  176. 176
    Wang, Q.; Wang, S.; Shi, Y.; Yao, M.; Hou, L.; Jiang, L. Reduction of Liver X Receptor β Expression in Primary Rat Neurons by Antisense Oligodeoxynucleotides Decreases Secreted Amyloid β Levels. Neurosci. Lett. 2014, 561, 146150,  DOI: 10.1016/j.neulet.2013.12.055
  177. 177
    Vanmierlo, T.; Rutten, K.; Dederen, J.; Bloks, V. W.; van Vark-van der Zee, L. C.; Kuipers, F.; Kiliaan, A.; Blokland, A.; Sijbrands, E. J. G.; Steinbusch, H.; Prickaerts, J.; Lütjohann, D.; Mulder, M. Liver X Receptor Activation Restores Memory in Aged AD Mice without Reducing Amyloid. Neurobiol. Aging 2011, 32 (7), 12621272,  DOI: 10.1016/j.neurobiolaging.2009.07.005
  178. 178
    Sandoval-Hernández, A. G.; Buitrago, L.; Moreno, H.; Cardona-Gómez, G. P.; Arboleda, G. Role of Liver X Receptor in AD Pathophysiology. PLoS One 2015, 10 (12), e0145467,  DOI: 10.1371/journal.pone.0145467
  179. 179
    Báez-Becerra, C.; Filipello, F.; Sandoval-Hernández, A.; Arboleda, H.; Arboleda, G. Liver X Receptor Agonist GW3965 Regulates Synaptic Function upon Amyloid Beta Exposure in Hippocampal Neurons. Neurotoxic. Res. 2018, 33 (4), 569579,  DOI: 10.1007/s12640-017-9845-3
  180. 180
    Kumar, N.; Solt, L. A.; Conkright, J. J.; Wang, Y.; Istrate, M. A.; Busby, S. A.; Garcia-Ordonez, R. D.; Burris, T. P.; Griffin, P. R. The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2- Trifluoro-1-Hydroxy-1-(Trifluoromethyl)Ethyl]Phenyl]-Benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist. Mol. Pharmacol. 2010, 77 (2), 228236,  DOI: 10.1124/mol.109.060905
  181. 181
    Dai, Y.-B.; Tan, X.-J.; Wu, W.-F.; Warner, M.; Gustafsson, J.-Å. Liver X Receptor β Protects Dopaminergic Neurons in a Mouse Model of Parkinson Disease. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (32), 1311213117,  DOI: 10.1073/pnas.1210833109
  182. 182
    Nelissen, K.; Mulder, M.; Smets, I.; Timmermans, S.; Smeets, K.; Ameloot, M.; Hendriks, J. J. A. Liver X Receptors Regulate Cholesterol Homeostasis in Oligodendrocytes. J. Neurosci. Res. 2012, 90 (1), 6071,  DOI: 10.1002/jnr.22743
  183. 183
    Berghoff, S. A.; Spieth, L.; Sun, T.; Hosang, L.; Schlaphoff, L.; Depp, C.; Düking, T.; Winchenbach, J.; Neuber, J.; Ewers, D.; Scholz, P.; van der Meer, F.; Cantuti-Castelvetri, L.; Sasmita, A. O.; Meschkat, M.; Ruhwedel, T.; Möbius, W.; Sankowski, R.; Prinz, M.; Huitinga, I.; Sereda, M. W.; Odoardi, F.; Ischebeck, T.; Simons, M.; Stadelmann-Nessler, C.; Edgar, J. M.; Nave, K.-A.; Saher, G. Microglia Facilitate Repair of Demyelinated Lesions via Post-Squalene Sterol Synthesis. Nat. Neurosci. 2021, 24 (1), 4760,  DOI: 10.1038/s41593-020-00757-6
  184. 184
    Mailleux, J.; Vanmierlo, T.; Bogie, J. F. J.; Wouters, E.; Lütjohann, D.; Hendriks, J. J. A.; van Horssen, J. Active Liver X Receptor Signaling in Phagocytes in Multiple Sclerosis Lesions. Mult. Scler. J. 2018, 24 (3), 279289,  DOI: 10.1177/1352458517696595
  185. 185
    Cui, G.; Qin, X.; Wu, L.; Zhang, Y.; Sheng, X.; Yu, Q.; Sheng, H.; Xi, B.; Zhang, J. Z.; Zang, Y. Q. Liver X Receptor (LXR) Mediates Negative Regulation of Mouse and Human Th17 Differentiation. J. Clin. Invest. 2011, 121 (2), 658670,  DOI: 10.1172/JCI42974
  186. 186
    Schultz, J. R.; Tu, H.; Luk, A.; Repa, J. J.; Medina, J. C.; Li, L.; Schwendner, S.; Wang, S.; Thoolen, M.; Mangelsdorf, D. J.; Lustig, K. D.; Shan, B. Role of LXRs in Control of Lipogenesis. Genes Dev. 2000, 14 (22), 28312838,  DOI: 10.1101/gad.850400
  187. 187
    Collins, J. L.; Fivush, A. M.; Watson, M. A.; Galardi, C. M.; Lewis, M. C.; Moore, L. B.; Parks, D. J.; Wilson, J. G.; Tippin, T. K.; Binz, J. G.; Plunket, K. D.; Morgan, D. G.; Beaudet, E. J.; Whitney, K. D.; Kliewer, S. A.; Willson, T. M. Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines. J. Med. Chem. 2002, 45 (10), 19631966,  DOI: 10.1021/jm0255116
  188. 188
    Kirchgessner, T. G.; Martin, R.; Sleph, P.; Grimm, D.; Liu, X.; Lupisella, J.; Smalley, J.; Narayanan, R.; Xie, Y.; Ostrowski, J.; Cantor, G. H.; Mohan, R.; Kick, E. Pharmacological Characterization of a Novel Liver X Receptor Agonist with Partial LXRα Activity and a Favorable Window in Nonhuman Primates. J. Pharmacol. Exp. Ther. 2015, 352 (2), 305314,  DOI: 10.1124/jpet.114.219923
  189. 189
    Wrobel, J.; Steffan, R.; Bowen, S. M.; Magolda, R.; Matelan, E.; Unwalla, R.; Basso, M.; Clerin, V.; Gardell, S. J.; Nambi, P.; Quinet, E.; Reminick, J. I.; Vlasuk, G. P.; Wang, S.; Feingold, I.; Huselton, C.; Bonn, T.; Farnegardh, M.; Hansson, T.; Nilsson, A. G.; Wilhelmsson, A.; Zamaratski, E.; Evans, M. J. Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride Synthesis. J. Med. Chem. 2008, 51 (22), 71617168,  DOI: 10.1021/jm800799q
  190. 190
    Stachel, S. J.; Zerbinatti, C.; Rudd, M. T.; Cosden, M.; Suon, S.; Nanda, K. K.; Wessner, K.; Dimuzio, J.; Maxwell, J.; Wu, Z.; Uslaner, J. M.; Michener, M. S.; Szczerba, P.; Brnardic, E.; Rada, V.; Kim, Y.; Meissner, R.; Wuelfing, P.; Yuan, Y.; Ballard, J.; Holahan, M.; Klein, D. J.; Lu, J.; Fradera, X.; Parthasarathy, G.; Uebele, V. N.; Chen, Z.; Li, Y.; Li, J.; Cooke, A. J.; Bennett, D. J.; Bilodeau, M. T.; Renger, J. Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease. J. Med. Chem. 2016, 59 (7), 34893498,  DOI: 10.1021/acs.jmedchem.6b00176
  191. 191
    Gezen-Ak, D.; Dursun, E. Molecular Basis of Vitamin D Action in Neurodegeneration: The Story of a Team Perspective. Hormones 2019, 18 (3), 1721,  DOI: 10.1007/s42000-018-0087-4
  192. 192
    Makishima, M.; Lu, T. T.; Xie, W.; Whitfield, G. K.; Domoto, H.; Evans, R. M.; Haussler, M. R.; Mangelsdorf, D. J. Vitamin D Receptor as an Intestinal Bile Acid Sensor. Science 2002, 296 (5571), 13131316,  DOI: 10.1126/science.1070477
  193. 193
    Yao, B.; He, J.; Yin, X.; Shi, Y.; Wan, J.; Tian, Z. The Protective Effect of Lithocholic Acid on the Intestinal Epithelial Barrier Is Mediated by the Vitamin D Receptor via a SIRT1/Nrf2 and NF-KB Dependent Mechanism in Caco-2 Cells. Toxicol. Lett. 2019, 316, 109118,  DOI: 10.1016/j.toxlet.2019.08.024
  194. 194
    Eyles, D. W.; Smith, S.; Kinobe, R.; Hewison, M.; McGrath, J. J. Distribution of the Vitamin D Receptor and 1α-Hydroxylase in Human Brain. J. Chem. Neuroanat. 2005, 29 (1), 2130,  DOI: 10.1016/j.jchemneu.2004.08.006
  195. 195
    Burne, T. H. J.; McGrath, J. J.; Eyles, D. W.; Mackay-Sim, A. Behavioural Characterization of Vitamin D Receptor Knockout Mice. Behav. Brain Res. 2005, 157 (2), 299308,  DOI: 10.1016/j.bbr.2004.07.008
  196. 196
    Beecham, G. W.; Martin, E. R.; Li, Y. J.; Slifer, M. A.; Gilbert, J. R.; Haines, J. L.; Pericak-Vance, M. A. Genome-Wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease. Am. J. Hum. Genet. 2009, 84 (1), 3543,  DOI: 10.1016/j.ajhg.2008.12.008
  197. 197
    Butler, M. W.; Burt, A.; Edwards, T. L.; Zuchner, S.; Scott, W. K.; Martin, E. R.; Vance, J. M.; Wang, L. Vitamin D Receptor Gene as a Candidate Gene for Parkinson Disease. Ann. Hum. Genet. 2011, 75 (2), 201210,  DOI: 10.1111/j.1469-1809.2010.00631.x
  198. 198
    Kim, J.-S.; Kim, Y.-I.; Song, C.; Yoon, I.; Park, J.-W.; Choi, Y.-B.; Kim, H.-T.; Lee, K.-S. Association of Vitamin D Receptor Gene Polymorphism and Parkinson’s Disease in Koreans. J. Korean Med. Sci. 2005, 20 (3), 495498,  DOI: 10.3346/jkms.2005.20.3.495
  199. 199
    Niino, M.; Miyazaki, Y. Genetic Polymorphisms Related to Vitamin D and the Therapeutic Potential of Vitamin D in Multiple Sclerosis. Can. J. Physiol. Pharmacol. 2015, 93 (5), 319325,  DOI: 10.1139/cjpp-2014-0374
  200. 200
    Vinh quôc Luong, K.; Thi Hoàng Nguyên, L. Vitamin D and Parkinson’s Disease. J. Neurosci Res. 2012, 90, 22272236,  DOI: 10.1002/jnr.23115
  201. 201
    Banerjee, A.; Khemka, V. K.; Ganguly, A.; Roy, D.; Ganguly, U.; Chakrabarti, S. Vitamin D and Alzheimer’s Disease: Neurocognition to Therapeutics. Int. J. Alzheimer's Dis. 2015, 2015, 192747,  DOI: 10.1155/2015/192747
  202. 202
    Luong, K.; Nguyen, L. Role of Vitamin D in Parkinson’s Disease. ISRN Neurol. 2012, 2012, 134289  DOI: 10.5402/2012/134289
  203. 203
    Munger, K. L.; Levin, L. I.; Hollis, B. W.; Howard, N. S.; Ascherio, A. Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis. J. Am. Med. Assoc. 2006, 296 (23), 28322838,  DOI: 10.1001/jama.296.23.2832
  204. 204
    Moretti, R.; Morelli, M. E.; Caruso, P. Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact. Int. J. Mol. Sci. 2018, 19 (8), 2245,  DOI: 10.3390/ijms19082245
  205. 205
    Salzer, J.; Hallmans, G.; Nyström, M.; Stenlund, H.; Wadell, G.; Sundström, P. Vitamin D as a Protective Factor in Multiple Sclerosis. Neurology 2012, 79 (21), 21402145,  DOI: 10.1212/WNL.0b013e3182752ea8
  206. 206
    Grimm, M. O. W.; Lauer, A. A.; Grösgen, S.; Thiel, A.; Lehmann, J.; Winkler, J.; Janitschke, D.; Herr, C.; Beisswenger, C.; Bals, R.; Grimm, H. S.; Hartmann, T. Profiling of Alzheimer’s Disease Related Genes in Mild to Moderate Vitamin D Hypovitaminosis. J. Nutr. Biochem. 2019, 67, 123137,  DOI: 10.1016/j.jnutbio.2019.01.015
  207. 207
    Uberti, F.; Morsanuto, V.; Bardelli, C.; Molinari, C. Protective Effects of 1α,25-Dihydroxyvitamin D3 on Cultured Neural Cells Exposed to Catalytic Iron. Physiol. Rep. 2016, 4 (11), e12769,  DOI: 10.14814/phy2.12769
  208. 208
    Ibi, M.; Sawada, H.; Nakanishi, M.; Kume, T.; Katsuki, H.; Kaneko, S.; Shimohama, S.; Akaike, A. Protective Effects of 1α,25-(OH)2D3 against the Neurotoxicity of Glutamate and Reactive Oxygen Species in Mesencephalic Culture. Neuropharmacology 2001, 40 (6), 761771,  DOI: 10.1016/S0028-3908(01)00009-0
  209. 209
    Zhang, D.; Li, M.; Dong, Y.; Zhang, X.; Liu, X.; Chen, Z.; Zhu, Y.; Wang, H.; Liu, X.; Zhu, J.; Shen, Y.; Korner, H.; Ying, S.; Fang, S.; Shen, Y. 1α,25-Dihydroxyvitamin D3 up-Regulates IL-34 Expression in SH-SY5Y Neural Cells. Innate Immun. 2017, 23 (7), 584591,  DOI: 10.1177/1753425917725391
  210. 210
    Jiao, K.-P.; Li, S.-M.; Lv, W.-Y.; Jv, M.-L.; He, H.-Y. Vitamin D3 Repressed Astrocyte Activation Following Lipopolysaccharide Stimulation in Vitro and in Neonatal Rats. NeuroReport 2017, 28 (9), 492497,  DOI: 10.1097/WNR.0000000000000782
  211. 211
    Dursun, E.; Gezen-Ak, D.; Yilmazer, S. A Novel Perspective for Alzheimer’s Disease: Vitamin D Receptor Suppression by Amyloid-β and Preventing the Amyloid-β Induced Alterations by Vitamin D in Cortical Neurons. Journal of Alzheimer’s Disease 2011, 23 (2), 207219,  DOI: 10.3233/JAD-2010-101377
  212. 212
    Niino, M. Vitamin D and Its Immunoregulatory Role in Multiple Sclerosis. Drugs Today (Barc) 2010, 46 (4), 279290,  DOI: 10.1358/dot.2010.46.4.1476498
  213. 213
    Kim, H.; Shin, J.-Y.; Lee, Y.-S.; Yun, S. P.; Maeng, H.-J.; Lee, Y. Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson’s Disease via a Vitamin D Receptor-Dependent Pathway. Int. J. Mol. Sci. 2020, 21 (22), 8538,  DOI: 10.3390/ijms21228538
  214. 214
    Maestro, M. A.; Molnár, F.; Carlberg, C. Vitamin D and Its Synthetic Analogs. J. Med. Chem. 2019, 62 (15), 68546875,  DOI: 10.1021/acs.jmedchem.9b00208
  215. 215
    Bishop, J. E.; Collins, E. D.; Okamura, W. H.; Norman, A. W. Profile of Ligand Specificity of the Vitamin D Binding Protein for 1α,25-dihydroxyvitamin D3 and Its Analogs. J. Bone Miner. Res. 1994, 9 (8), 12771288,  DOI: 10.1002/jbmr.5650090818
  216. 216
    Saito, N.; Matsunaga, T.; Saito, H.; Anzai, M.; Takenouchi, K.; Miura, D.; Namekawa, J.; Ishizuka, S.; Kittaka, A. Further Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α- Hydroxyvitamin D3–26,23-Lactones. J. Med. Chem. 2006, 49 (24), 70637075,  DOI: 10.1021/jm060797q
  217. 217
    Wiberg, K.; Ljunghall, S.; Binderup, L.; Ljunggren, Ö. Studies on Two New Vitamin D Analogs, EB 1089 and KH 1060: Effects on Bone Resorption and Osteoclast Recruitment in Vitro. Bone 1995, 17 (4), 391395,  DOI: 10.1016/S8756-3282(95)00246-4
  218. 218
    Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M. A.; Leid, M.; De Lera, A. R.; Lotan, R.; Mangelsdorf, D. J.; Gronemeyer, H. International Union of Pharmacology. LXIII. Retinoid X Receptors. Pharmacol. Rev. 2006, 58 (4), 760772,  DOI: 10.1124/pr.58.4.7
  219. 219
    de Lera, A. R.; Bourguet, W.; Altucci, L.; Gronemeyer, H. Design of Selective Nuclear Receptor Modulators: RAR and RXR as a Case Study. Nat. Rev. Drug Discovery 2007, 6 (10), 811820,  DOI: 10.1038/nrd2398
  220. 220
    Dominguez, M.; Alvarez, S.; de Lera, A. R. Natural and Structure-Based RXR Ligand Scaffolds and Their Functions. Curr. Top. Med. Chem. 2017, 17 (6), 631662,  DOI: 10.2174/1568026616666160617072521
  221. 221
    Chaikuad, A.; Pollinger, J.; Rühl, M.; Ni, X.; Kilu, W.; Heering, J.; Merk, D. Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms. Int. J. Mol. Sci. 2020, 21 (22), 8457,  DOI: 10.3390/ijms21228457
  222. 222
    Schierle, S.; Merk, D. Therapeutic Modulation of Retinoid X Receptors - SAR and Therapeutic Potential of RXR Ligands and Recent Patents. Expert Opin. Ther. Pat. 2019, 29 (8), 605621,  DOI: 10.1080/13543776.2019.1643322
  223. 223
    Egea, P. F.; Mitschler, A.; Moras, D. Molecular Recognition of Agonist Ligands by RXRs. Mol. Endocrinol. 2002, 16 (5), 987997,  DOI: 10.1210/mend.16.5.0823
  224. 224
    Zetterstrom, R. H.; Lindqvist, E.; De Urquiza, A. M.; Tomac, A.; Eriksson, U.; Perlmann, T.; Olson, L. Role of Retinoids in the CNS : Differential Expression of Retinoid Binding Proteins and Receptors and Evidence for Presence of Retinoic Acid. Eur. J. Neurosci. 1999, 11 (2), 407416,  DOI: 10.1046/j.1460-9568.1999.00444.x
  225. 225
    Ferré, S.; Fredholm, B. B.; Morelli, M.; Popoli, P.; Fuxe, K. Adenosine – Dopamine Receptor – Receptor Interactions as an Integrative Mechanism in the Basal Ganglia. Trends Neurosci. 1997, 20 (10), 482487,  DOI: 10.1016/S0166-2236(97)01096-5
  226. 226
    Moreno, S.; Farioli-Vecchioli, S.; Cerù, M. P. Immunolocalization of Peroxisome Proliferator-Activated Receptors and Retinoid X Receptors in the Adult Rat CNS. Neuroscience 2004, 123 (1), 131145,  DOI: 10.1016/j.neuroscience.2003.08.064
  227. 227
    Huang, J. K.; Jarjour, A. A.; Nait Oumesmar, B.; Kerninon, C.; Williams, A.; Krezel, W.; Kagechika, H.; Bauer, J.; Zhao, C.; Baron-Van Evercooren, A.; Chambon, P.; Ffrench-Constant, C.; Franklin, R. J. M. Retinoid X Receptor Gamma Signaling Accelerates CNS Remyelination. Nat. Neurosci. 2011, 14 (1), 4553,  DOI: 10.1038/nn.2702
  228. 228
    Hanafy, K. A.; Sloane, J. A. Regulation of Remyelination in Multiple Sclerosis. FEBS Lett. 2011, 585 (23), 38213828,  DOI: 10.1016/j.febslet.2011.03.048
  229. 229
    Vaz, B.; de Lera, Á. R. Advances in Drug Design with RXR Modulators. Expert Opin. Drug Discovery 2012, 7 (11), 10031016,  DOI: 10.1517/17460441.2012.722992
  230. 230
    Koster, K. P.; Smith, C.; Valencia-Olvera, A. C.; Thatcher, G. R. J.; Tai, L. M.; LaDu, M. J. Rexinoids as Therapeutics for Alzheimer’s Disease: Role of APOE. Curr. Top. Med. Chem. 2017, 17 (6), 708720,  DOI: 10.2174/1568026616666160617090227
  231. 231
    Corder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel, D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.; Pericak-Vance, M. A. Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer’s Disease in Late Onset Families. Science 1993, 261 (5123), 921923,  DOI: 10.1126/science.8346443
  232. 232
    Cosentino, S.; Scarmeas, N.; Helzner, E.; Glymour, M. M.; Brandt, J.; Albert, M.; Blacker, D.; Stern, Y. APOE Epsilon 4 Allele Predicts Faster Cognitive Decline in Mild Alzheimer Disease. Neurology 2008, 70 (19), 18421849,  DOI: 10.1212/01.wnl.0000304038.37421.cc
  233. 233
    Khachaturian, A. S.; Corcoran, C. D.; Mayer, L. S.; Zandi, P. P.; Breitner, J. C. S. Apolipoprotein E Epsilon4 Count Affects Age at Onset of Alzheimer Disease, but Not Lifetime Susceptibility: The Cache County Study. Arch. Gen. Psychiatry 2004, 61 (5), 518524,  DOI: 10.1001/archpsyc.61.5.518
  234. 234
    Mandrekar-Colucci, S.; Landreth, G. E. Nuclear Receptors as Therapeutic Targets for Alzheimer’s Disease. Expert Opin. Ther. Targets 2011, 15 (9), 10851097,  DOI: 10.1517/14728222.2011.594043
  235. 235
    Koldamova, R.; Fitz, N. F.; Lefterov, I. ATP-Binding Cassette Transporter A1: From Metabolism to Neurodegeneration. Neurobiol. Dis. 2014, 72A, 1321,  DOI: 10.1016/j.nbd.2014.05.007
  236. 236
    Oram, J. F.; Vaughan, A. M. ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease. Circ. Res. 2006, 99 (10), 10311043,  DOI: 10.1161/01.RES.0000250171.54048.5c
  237. 237
    Tai, L. M.; Mehra, S.; Shete, V.; Estus, S.; Rebeck, G. W.; Bu, G.; Ladu, M. J. Soluble ApoE/Aβ Complex: Mechanism and Therapeutic Target for APOE4-Induced AD Risk. Mol. Neurodegener. 2014, 9, 2,  DOI: 10.1186/1750-1326-9-2
  238. 238
    Yu, C.; Youmans, K. L.; Ladu, M. J. Proposed Mechanism for Lipoprotein Remodelling in the Brain. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2010, 1801 (8), 819823,  DOI: 10.1016/j.bbalip.2010.05.001
  239. 239
    Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo, J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L.; Goebel, W. D.; James, M. J.; Brunden, K. R.; Wilson, D. A.; Landreth, G. E. ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models. Science 2012, 335 (6075), 15031506,  DOI: 10.1126/science.1217697
  240. 240
    Fitz, N. F.; Cronican, A. A.; Lefterov, I.; Koldamova, R. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924c,  DOI: 10.1126/science.1235809
  241. 241
    Price, A. R.; Xu, G.; Siemienski, Z. B.; Smithson, L. A.; Borchelt, D. R.; Golde, T. E.; Felsenstein, K. M. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924d,  DOI: 10.1126/science.1234089
  242. 242
    Tesseur, I.; Lo, A. C.; Roberfroid, A.; Dietvorst, S.; Van Broeck, B.; Borgers, M.; Gijsen, H.; Moechars, D.; Mercken, M.; Kemp, J.; D'Hooge, R.; De Strooper, B. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924-e,  DOI: 10.1126/science.1233937
  243. 243
    Veeraraghavalu, K.; Zhang, C.; Miller, S.; Hefendehl, J. K.; Rajapaksha, T. W.; Ulrich, J.; Jucker, M.; Holtzman, D. M.; Tanzi, R. E.; Vassar, R.; Sisodia, S. S. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924f,  DOI: 10.1126/science.1235505
  244. 244
    Ghosal, K.; Haag, M.; Verghese, P. B.; West, T.; Veenstra, T.; Braunstein, J. B.; Bateman, R. J.; Holtzman, D. M.; Landreth, G. E. A Randomized Controlled Study to Evaluate the Effect of Bexarotene on Amyloid-β and Apolipoprotein E Metabolism in Healthy Subjects. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2016, 2 (2), 110120,  DOI: 10.1016/j.trci.2016.06.001
  245. 245
    Cummings, J. L.; Zhong, K.; Kinney, J. W.; Heaney, C.; Moll-Tudla, J.; Joshi, A.; Pontecorvo, M.; Devous, M.; Tang, A.; Bena, J. Double-Blind, Placebo-Controlled, Proof-of-Concept Trial of Bexarotene in Moderate Alzheimer’s Disease. Alzheimer’s Res. Ther. 2016, 8 (4), 4,  DOI: 10.1186/s13195-016-0173-2
  246. 246
    Lammi, J.; Perlmann, T.; Aarnisalo, P. Corepressor Interaction Differentiates the Permissive and Non-Permissive Retinoid X Receptor Heterodimers. Arch. Biochem. Biophys. 2008, 472 (2), 105114,  DOI: 10.1016/j.abb.2008.02.003
  247. 247
    Schrage, K.; Koopmans, G.; Joosten, E. A. J.; Mey, J. Macrophages and Neurons Are Targets of Retinoic Acid Signaling after Spinal Cord Contusion Injury. Eur. J. Neurosci. 2006, 23 (2), 285295,  DOI: 10.1111/j.1460-9568.2005.04534.x
  248. 248
    Natrajan, M. S.; de la Fuente, A. G.; Crawford, A. H.; Linehan, E.; Nuñez, V.; Johnson, K. R.; Wu, T.; Fitzgerald, D. C.; Ricote, M.; Bielekova, B.; Franklin, R. J. M. Retinoid X Receptor Activation Reverses Age-Related Deficiencies in Myelin Debris Phagocytosis and Remyelination. Brain 2015, 138 (12), 35813597,  DOI: 10.1093/brain/awv289
  249. 249
    Baer, A. S.; Syed, Y. A.; Kang, S. U.; Mitteregger, D.; Vig, R.; Ffrench-Constant, C.; Franklin, R. J. M.; Altmann, F.; Lubec, G.; Kotter, M. R. Myelin-Mediated Inhibition of Oligodendrocyte Precursor Differentiation Can Be Overcome by Pharmacological Modulation of Fyn-RhoA and Protein Kinase C Signalling. Brain 2009, 132 (2), 465481,  DOI: 10.1093/brain/awn334
  250. 250
    Kotter, M. R.; Zhao, C.; van Rooijen, N.; Franklin, R. J.M. Macrophage-Depletion Induced Impairment of Experimental CNS Remyelination Is Associated with a Reduced Oligodendrocyte Progenitor Cell Response and Altered Growth Factor Expression. Neurobiol. Dis. 2005, 18 (1), 166175,  DOI: 10.1016/j.nbd.2004.09.019
  251. 251
    Xu, J.; Drew, P. D. 9-Cis-Retinoic Acid Suppresses Inflammatory Responses of Microglia and Astrocytes. J. Neuroimmunol. 2006, 171 (1–2), 135144,  DOI: 10.1016/j.jneuroim.2005.10.004
  252. 252
    Chandraratna, R. A.; Sanders, M. E. WO2017/075607 Treatment of Nervous System Disorders Using Combinations of RXR Agonists and Thyroid Hormones, IO Ther. INC, 2017.
  253. 253
    Volle, D. H. Nuclear Receptors as Pharmacological Targets, Where Are We Now?. Cell. Mol. Life Sci. 2016, 73 (10), 37773780,  DOI: 10.1007/s00018-016-2327-6
  254. 254
    Levin, A. A.; Sturzenbecker, L. J.; Kazmer, S.; Bosakowski, T.; Huselton, C.; Allenby, G.; Speck, J.; Kratzeisen, C.; Rosenberger, M.; Lovey, A.; Grippo, J. F. 9-Cis Retinoic Acid Stereoisomer Binds and Activates the Nuclear Receptor RXR Alpha. Nature 1992, 355 (6358), 359361,  DOI: 10.1038/355359a0
  255. 255
    Goldstein, J. T.; Dobrzyn, A.; Clagett-Dame, M.; Pike, J. W.; Deluca, H. F. Isolation and Characterization of Unsaturated Fatty Acids as Natural Ligands for the Retinoid-X Receptor. Arch. Biochem. Biophys. 2003, 420 (1), 185193,  DOI: 10.1016/j.abb.2003.09.034
  256. 256
    Fitzgerald, P.; Teng, M.; Chandraratna, R. A. S.; Heyman, A.; Allegretto, A. Retinoic Acid Receptor α Expression Correlates with Retinoid-Induced Growth Inhibition of Human Breast Cancer Cells Regardless of Estrogen Receptor Status. Cancer Res. 1997, 57 (13), 26422650
  257. 257
    Vuligonda, V.; Thacher, S. M.; Chandraratna, R. A. Enantioselective Syntheses of Potent Retinoid X Receptor Ligands: Differential Biological Activities of Individual Antipodes. J. Med. Chem. 2001, 44 (14), 22982303,  DOI: 10.1021/jm0100584
  258. 258
    Boehm, M. F.; McClurg, M. R.; Pathirana, C.; Mangelsdorf, D.; White, S. K.; Hebert, J.; Winn, D.; Goldman, M. E.; Heyman, R. A. Synthesis of High Specific Activity [3H]-9-Cis-Retinoic Acid and Its Application for Identifying Retinoids with Unusual Binding Properties. J. Med. Chem. 1994, 37 (3), 408414,  DOI: 10.1021/jm00029a013
  259. 259
    Blair, H. A.; Scott, L. J. Alitretinoin : A Review in Severe Chronic Hand Eczema. Drugs 2016, 76 (13), 12711279,  DOI: 10.1007/s40265-016-0621-0
  260. 260
    Cheer, S. M.; Foster, R. H. Alitretinoin. Am. J. Clin. Dermatol. 2000, 1 (5), 307314,  DOI: 10.2165/00128071-200001050-00005
  261. 261
    Son, J. H.; Park, S. Y.; Cho, Y. S.; Byun, Y. S.; Chung, B. Y.; Cho, H. J.; Kim, H. O.; Park, C. W. Two Cases of Successful Treatment of Refractory Chronic Inflammatory Skin Disease, Atopic Dermatitis and Psoriasis with Oral Alitretinoin. Ann. Dermatol. 2017, 29 (4), 503506,  DOI: 10.5021/ad.2017.29.4.503
  262. 262
    Rühl, R.; Krzyzosiak, A.; Niewiadomska-Cimicka, A.; Rochel, N.; Szeles, L.; Vaz, B.; Wietrzych-Schindler, M.; Álvarez, S.; Szklenar, M.; Nagy, L.; de Lera, A. R.; Krezel, W. 9-Cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice. PLoS Genet. 2015, 11 (6), e1005213,  DOI: 10.1371/journal.pgen.1005213
  263. 263
    de Lera, Á.; Krezel, W.; Rühl, R. An Endogenous Mammalian Retinoid X Receptor Ligand, at Last!. ChemMedChem 2016, 11 (10), 10271037,  DOI: 10.1002/cmdc.201600105
  264. 264
    Neuringer, M.; Anderson, G. J.; Connor, W. E. The Essentiality of N-3 Fatty Acids for the Development and Function of the Retina and Brain. Annu. Rev. Nutr. 1988, 8, 517541,  DOI: 10.1146/annurev.nu.08.070188.002505
  265. 265
    Bourguet, W.; Vivat, V.; Wurtz, J.-M.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal Structure of a Heterodimeric Complex of RAR and RXR Ligand-Binding Domains. Mol. Cell 2000, 5 (2), 289298,  DOI: 10.1016/S1097-2765(00)80424-4
  266. 266
    Heald, P.; Mehlmauer, M.; Martin, A. G.; Crowley, C. A.; Yocum, R. C.; Reich, S. D. Topical Bexarotene Therapy for Patients with Refractory or Persistent Early-Stage Cutaneous T-Cell Lymphoma: Results of the Phase III Clinical Trial. J. Am. Acad. Dermatol. 2003, 49 (5), 801815,  DOI: 10.1016/S0190-9622(03)01475-0
  267. 267
    Wong, S. F. Oral Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma. Ann. Pharmacother. 2001, 35 (9), 10561065,  DOI: 10.1345/aph.10223
  268. 268
    Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.; Mais, D. E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A. Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective Retinoids. J. Med. Chem. 1994, 37 (18), 29302941,  DOI: 10.1021/jm00044a014
  269. 269
    Howell, S. R.; Shirley, M. A.; Grese, T. A.; Neel, D. A.; Wells, K. E.; Ulm, E. H. Bexarotene Metabolism in Rat, Dog, and Human, Synthesis of Oxidative Metabolites, and in Vitro Activity at Retinoid Receptors. Drug Metab. Dispos. 2001, 29 (7), 990998
  270. 270
    Wang, Y.; Rong, J.; Zhang, J.; Liu, Y.; Meng, X.; Guo, H.; Liu, H.; Chen, L. Morphology, in Vivo Distribution and Antitumor Activity of Bexarotene Nanocrystals in Lung Cancer. Drug Dev. Ind. Pharm. 2017, 43 (1), 132141,  DOI: 10.1080/03639045.2016.1225752
  271. 271
    Lowenthal, J.; Hull, S. C.; Pearson, S. D. The Ethics of Early Evidence - Preparing for a Possible Breakthrough in Alzheimer’s Disease. N. Engl. J. Med. 2012, 367 (6), 488490,  DOI: 10.1056/NEJMp1203104
  272. 272
    Takamatsu, K.; Takano, A.; Yakushiji, N.; Morishita, K.; Matsuura, N.; Makishima, M.; Ali, H. I.; Akaho, E.; Tai, A.; Sasaki, K.; Kakuta, H. Reduction of Lipophilicity at the Lipophilic Domain of RXR Agonists Enables Production of Subtype Preference: RXRa- Preferential Agonist Possessing a Sulfonamide Moiety. ChemMedChem 2008, 3 (3), 454460,  DOI: 10.1002/cmdc.200700265
  273. 273
    Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, M. R.; Berger, E.; Wagoner, M.; Mais, D. E.; Suto, C. M.; Davies, P. J. A.; Heyman, R. A.; Nadzan, A. M. Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells. J. Med. Chem. 1995, 38 (16), 31463155,  DOI: 10.1021/jm00016a018
  274. 274
    Takamatsu, K.; Takano, A.; Yakushiji, N.; Morohashi, K.; Morishita, K.; Matsuura, N.; Makishima, M.; Tai, A.; Sasaki, K.; Kakuta, H. The First Potent Subtype-Selective Retinoid X Receptor (RXR) Agonist Possessing a 3-Isopropoxy-4-isopropylphenylamino Moiety, NEt-3IP (RXRα/B-dual Agonist). ChemMedChem 2008, 3 (5), 780787,  DOI: 10.1002/cmdc.200700313
  275. 275
    Pollinger, J.; Merk, D. Therapeutic Applications of the Versatile Fatty Acid Mimetic WY14643. Expert Opin. Ther. Pat. 2017, 27 (4), 517525,  DOI: 10.1080/13543776.2017.1272578
  276. 276
    Watanabe, M.; Kakuta, H. Retinoid X Receptor Antagonists. Int. J. Mol. Sci. 2018, 19 (8), 2354  DOI: 10.3390/ijms19082354
  277. 277
    Nakayama, M.; Yamada, S.; Ohsawa, F.; Ohta, Y.; Kawata, K.; Makishima, M.; Kakuta, H. Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB. ACS Med. Chem. Lett. 2011, 2 (12), 896900,  DOI: 10.1021/ml200197e
  278. 278
    Merk, D.; Grisoni, F.; Friedrich, L.; Gelzinyte, E.; Schneider, G. Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional Mimetics. J. Med. Chem. 2018, 61 (12), 54425447,  DOI: 10.1021/acs.jmedchem.8b00494
  279. 279
    Merk, D.; Grisoni, F.; Friedrich, L.; Gelzinyte, E.; Schneider, G. Scaffold Hopping from Synthetic RXR Modulators by Virtual Screening and de Novo Design. MedChemComm 2018, 9, 12891292,  DOI: 10.1039/C8MD00134K
  280. 280
    Pollinger, J.; Schierle, S.; Gellrich, L.; Ohrndorf, J.; Kaiser, A.; Heitel, P.; Chaikuad, A.; Knapp, S.; Merk, D. A Novel Biphenyl-Based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences. ACS Med. Chem. Lett. 2019, 10 (9), 13461352,  DOI: 10.1021/acsmedchemlett.9b00306
  281. 281
    Islam, M. M.; Zhang, C.-L. TLX: A Master Regulator for Neural Stem Cell Maintenance and Neurogenesis. Biochim. Biophys. Acta, Gene Regul. Mech. 2015, 1849 (2), 210216,  DOI: 10.1016/j.bbagrm.2014.06.001
  282. 282
    Shi, Y.; Lie, D. C.; Taupin, P.; Nakashima, K.; Ray, J.; Yu, R. T.; Gage, F. H.; Evans, R. M. Expression and Function of Orphan Nuclear Receptor TLX in Adult Neural Stem Cells. Nature 2004, 427 (6969), 7883,  DOI: 10.1038/nature02211
  283. 283
    Miyawaki, T.; Uemura, A.; Dezawa, M.; Yu, R. T.; Ide, C.; Nishikawa, S.; Honda, Y.; Tanabe, Y.; Tanabe, T. Tlx, an Orphan Nuclear Receptor, Regulates Cell Numbers and Astrocyte Development in the Developing Retina. J. Neurosci. 2004, 24 (37), 81248134,  DOI: 10.1523/JNEUROSCI.2235-04.2004
  284. 284
    Monaghan, A. P.; Grau, E.; Bock, D.; Schütz, G. The Mouse Homolog of the Orphan Nuclear Receptor Tailless Is Expressed in the Developing Forebrain. Development 1995, 121 (3), 839853,  DOI: 10.1242/dev.121.3.839
  285. 285
    Li, S.; Sun, G.; Murai, K.; Ye, P.; Shi, Y. Characterization of TLX Expression in Neural Stem Cells and Progenitor Cells in Adult Brains. PLoS One 2012, 7 (8), e43324,  DOI: 10.1371/journal.pone.0043324
  286. 286
    Benod, C.; Villagomez, R.; Webb, P. TLX: An Elusive Receptor. J. Steroid Biochem. Mol. Biol. 2016, 157, 4147,  DOI: 10.1016/j.jsbmb.2015.11.001
  287. 287
    Yokoyama, A.; Takezawa, S.; Schule, R.; Kitagawa, H.; Kato, S. Transrepressive Function of TLX Requires the Histone Demethylase LSD1. Mol. Cell. Biol. 2008, 28 (12), 39954003,  DOI: 10.1128/MCB.02030-07
  288. 288
    Zhang, C.-L.; Zou, Y.; Yu, R. T.; Gage, F. H.; Evans, R. M. Nuclear Receptor TLX Prevents Retinal Dystrophy and Recruits the Corepressor Atrophin1. Genes Dev. 2006, 20 (10), 13081320,  DOI: 10.1101/gad.1413606
  289. 289
    Estruch, S. B.; Buzón, V.; Carbó, L. R.; Schorova, L.; Lüders, J.; Estébanez-Perpiñá, E. The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates Its Transrepressive Function. PLoS One 2012, 7 (6), e37963,  DOI: 10.1371/journal.pone.0037963
  290. 290
    Sun, G.; Yu, R. T.; Evans, R. M.; Shi, Y. Orphan Nuclear Receptor TLX Recruits Histone Deacetylases to Repress Transcription and Regulate Neural Stem Cell Proliferation. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (39), 1528215287,  DOI: 10.1073/pnas.0704089104
  291. 291
    Griffett, K.; Bedia-Diaz, G.; Hegazy, L.; de Vera, I. M. S.; Wanninayake, U. S.; Billon, C.; Koelblen, T.; Wilhelm, M. L.; Burris, T. P. The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids. Cell Chem. Biol. 2020, 27 (10), 12721284,  DOI: 10.1016/j.chembiol.2020.07.013
  292. 292
    Benod, C.; Villagomez, R.; Filgueira, C. S.; Hwang, P. K.; Leonard, P. G.; Poncet-Montange, G.; Rajagopalan, S.; Fletterick, R. J.; Gustafsson, J.-Å.; Webb, P. The Human Orphan Nuclear Receptor Tailless (TLX, NR2E1) Is Druggable. PLoS One 2014, 9 (6), e99440,  DOI: 10.1371/journal.pone.0099440
  293. 293
    Zhi, X.; Zhou, X. E.; He, Y.; Searose-Xu, K.; Zhang, C.-L.; Tsai, C.-C.; Melcher, K.; Xu, H. E. Structural Basis for Corepressor Assembly by the Orphan Nuclear Receptor TLX. Genes Dev. 2015, 29 (4), 440450,  DOI: 10.1101/gad.254904.114
  294. 294
    Tan, M. H. E.; Zhou, X. E.; Soon, F.-F.; Li, X.; Li, J.; Yong, E.-L.; Melcher, K.; Xu, H. E. The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation. PLoS One 2013, 8 (9), e74359,  DOI: 10.1371/journal.pone.0074359
  295. 295
    Sablin, E. P.; Woods, A.; Krylova, I. N.; Hwang, P.; Ingraham, H. A.; Fletterick, R. J. The Structure of Corepressor Dax-1 Bound to Its Target Nuclear Receptor LRH-1. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (47), 1839018395,  DOI: 10.1073/pnas.0808936105
  296. 296
    Kandel, P.; Semerci, F.; Bajic, A.; Baluya, D.; Ma, L.; Chen, K.; Cao, A.; Phongmekhin, T.; Matinyan, N.; Choi, W.; Jiménez-Panizo, A.; Chamakuri, S.; Raji, I. O.; Chang, L.; Fuentes-Prior, P.; MacKenzie, K. R.; Benn, C. L.; Estébanez-Perpiñá, E.; Venken, K.; Moore, D. D.; Young, D. W.; Maletic-Savatic, M. Oleic Acid Triggers Hippocampal Neurogenesis by Binding to TLX/NR2E1. bioRxiv 2020, 2020.10.28.359810.
  297. 297
    Niu, W.; Zou, Y.; Shen, C.; Zhang, C.-L. Activation of Postnatal Neural Stem Cells Requires Nuclear Receptor TLX. J. Neurosci. 2011, 31 (39), 1381613828,  DOI: 10.1523/JNEUROSCI.1038-11.2011
  298. 298
    Roy, K.; Kuznicki, K.; Wu, Q.; Sun, Z.; Bock, D.; Schutz, G.; Vranich, N.; Monaghan, A. P. The Tlx Gene Regulates the Timing of Neurogenesis in the Cortex. J. Neurosci. 2004, 24 (38), 83338345,  DOI: 10.1523/JNEUROSCI.1148-04.2004
  299. 299
    Shi, Y.; Sun, G.; Zhao, C.; Stewart, R. Neural Stem Cell Self-Renewal. Crit. Rev. Oncol. Hematol. 2008, 65 (1), 4353,  DOI: 10.1016/j.critrevonc.2007.06.004
  300. 300
    Elmi, M.; Matsumoto, Y.; Zeng, Z.; Lakshminarasimhan, P.; Yang, W.; Uemura, A.; Nishikawa, S.; Moshiri, A.; Tajima, N.; Agren, H.; Funa, K. TLX Activates MASH1 for Induction of Neuronal Lineage Commitment of Adult Hippocampal Neuroprogenitors. Mol. Cell. Neurosci. 2010, 45 (2), 121131,  DOI: 10.1016/j.mcn.2010.06.003
  301. 301
    Liu, H.-K.; Belz, T.; Bock, D.; Takacs, A.; Wu, H.; Lichter, P.; Chai, M.; Schütz, G. The Nuclear Receptor Tailless Is Required for Neurogenesis in the Adult Subventricular Zone. Genes Dev. 2008, 22 (18), 24732478,  DOI: 10.1101/gad.479308
  302. 302
    Monaghan, A. P.; Bock, D.; Gass, P.; Schwger, A.; Wolfer, D. P.; Lipp, H.-P.; Schütz, G. Defective Limbic System in Mice Lacking the Tailless Gene. Nature 1997, 390 (6659), 515517,  DOI: 10.1038/37364
  303. 303
    Yu, R. T.; Chiang, M.-Y.; Tanabe, T.; Kobayashi, M.; Yasuda, K.; Evans, R. M.; Umesono, K. The Orphan Nuclear Receptor Tlx Regulates Pax2 and Is Essential for Vision. Proc. Natl. Acad. Sci. U. S. A. 2000, 97 (6), 26212625,  DOI: 10.1073/pnas.050566897
  304. 304
    Juárez, P.; Valdovinos, M. G.; May, M. E.; Lloyd, B. P.; Couppis, M. H.; Kennedy, C. H. Serotonin2A/C Receptors Mediate the Aggressive Phenotype of TLX Gene Knockout Mice. Behav. Brain Res. 2013, 256, 354361,  DOI: 10.1016/j.bbr.2013.07.044
  305. 305
    Murai, K.; Qu, Q.; Sun, G.; Ye, P.; Li, W.; Asuelime, G.; Sun, E.; Tsai, G. E.; Shi, Y. Nuclear Receptor TLX Stimulates Hippocampal Neurogenesis and Enhances Learning and Memory in a Transgenic Mouse Model. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (25), 91159120,  DOI: 10.1073/pnas.1406779111
  306. 306
    O’Leary, J. D.; Kozareva, D. A.; Hueston, C. M.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. The Nuclear Receptor Tlx Regulates Motor, Cognitive and Anxiety-Related Behaviours during Adolescence and Adulthood. Behav. Brain Res. 2016, 306, 3647,  DOI: 10.1016/j.bbr.2016.03.022
  307. 307
    Kozareva, D. A.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. Deletion of TLX and Social Isolation Impairs Exercise-Induced Neurogenesis in the Adolescent Hippocampus. Hippocampus 2018, 28 (1), 311,  DOI: 10.1002/hipo.22805
  308. 308
    O’Leary, J. D.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. Regulation of Behaviour by the Nuclear Receptor TLX. Genes, Brain Behav. 2018, 17 (3), e12357,  DOI: 10.1111/gbb.12357
  309. 309
    Kumar, R. A.; McGhee, K. A.; Leach, S.; Bonaguro, R.; Maclean, A.; Aguirre-Hernandez, R.; Abrahams, B. S.; Coccaro, E. F.; Hodgins, S.; Turecki, G.; Condon, A.; Muir, W. J.; Brooks-Wilson, A. R.; Blackwood, D. H.; Simpson, E. M. Initial Association of NR2E1 with Bipolar Disorder and Identification of Candidate Mutations in Bipolar Disorder, Schizophrenia, and Aggression through Resequencing. Am. J. Med. Genet., Part B 2008, 147B (6), 880889,  DOI: 10.1002/ajmg.b.30696
  310. 310
    Wang, Y. Y.; Hsu, S. H.; Tsai, H. Y.; Cheng, M. C. Genetic Analysis of the NR2E1 Gene as a Candidate Gene of Schizophrenia. Psychiatry Res. 2020, 293, 113386,  DOI: 10.1016/j.psychres.2020.113386
  311. 311
    Liu, H. K.; Wang, Y.; Belz, T.; Bock, D.; Takacs, A.; Radlwimmer, B.; Barbus, S.; Reifenberger, G.; Lichter, P.; Schütz, G. The Nuclear Receptor Tailless Induces Long-Term Neural Stem Cell Expansion and Brain Tumor Initiation. Genes Dev. 2010, 24 (7), 683695,  DOI: 10.1101/gad.560310
  312. 312
    Park, H.-J.; Kim, J.-K.; Jeon, H.-M.; Oh, S.-Y.; Kim, S.-H.; Park, M.-J.; Soeda, A.; Nam, D.-H.; Kim, H. The Neural Stem Cell Fate Determinant TLX Promotes Tumorigenesis and Genesis of Cells Resembling Glioma Stem Cells. Mol. Cells 2010, 30 (5), 403408,  DOI: 10.1007/s10059-010-0122-z
  313. 313
    Louis, D. N.; Ohgaki, H.; Wiestler, O. D.; Cavenee, W. K.; Burger, P. C.; Jouvet, A.; Scheithauer, B. W.; Kleihues, P. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica 2007, 114, 97109
  314. 314
    Cui, Q.; Yang, S.; Ye, P.; Tian, E.; Sun, G.; Zhou, J.; Sun, G.; Liu, X.; Chen, C.; Murai, K.; Zhao, C.; Azizian, K. T.; Yang, L.; Warden, C.; Wu, X.; D’Apuzzo, M.; Brown, C.; Badie, B.; Peng, L.; Riggs, A. D.; Rossi, J. J.; Shi, Y. Downregulation of TLX Induces TET3 Expression and Inhibits Glioblastoma Stem Cell Self-Renewal and Tumorigenesis. Nat. Commun. 2016, 7, 10637,  DOI: 10.1038/ncomms10637
  315. 315
    Dueva, E.; Singh, K.; Kalyta, A.; LeBlanc, E.; Rennie, P. S.; Cherkasov, A. Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor. Molecules 2018, 23 (11), 2967,  DOI: 10.3390/molecules23112967
  316. 316
    Milbrandt, J. Nerve Growth Factor Induces a Gene Homologous to the Glucocorticoid Receptor Gene. Neuron 1988, 1 (3), 183188,  DOI: 10.1016/0896-6273(88)90138-9
  317. 317
    Wang, Z.; Benoit, G.; Liu, J.; Prasad, S.; Aarnisalo, P.; Liu, X.; Xu, H.; Walker, N. P. C.; Perlmann, T. Structure and Function of Nurr1 Identifies a Class of Ligand- Independent Nuclear Receptors. Nature 2003, 423 (6939), 555560,  DOI: 10.1038/nature01645
  318. 318
    Murphy, E. P.; Conneely, O. M. Neuroendocrine Regulation of the Hypothalamic Pituitary Adrenal Axis by the Nurr1/Nur77 Subfamily of Nuclear Receptors. Mol. Endocrinol. 1997, 11 (1), 3947,  DOI: 10.1210/mend.11.1.9874
  319. 319
    Paulsen, R. E.; Granås, K.; Johnsen, H.; Rolseth, V.; Sterri, S. Three Related Brain Nuclear Receptors, NGFI-B, Nurr1, and NOR-1, as Transcriptional Activators. J. Mol. Neurosci. 1995, 6 (4), 249255,  DOI: 10.1007/BF02736784
  320. 320
    Maira, M.; Martens, C.; Philips, A.; Drouin, J. Heterodimerization between Members of the Nur Subfamily of Orphan Nuclear Receptors as a Novel Mechanism for Gene Activation. Mol. Cell. Biol. 1999, 19 (11), 75497557,  DOI: 10.1128/MCB.19.11.7549
  321. 321
    Perlmann, T.; Jansson, L. A Novel Pathway for Vitamin A Signaling Mediated by RXR Heterodimerization with NGFI-B and NURR1. Genes Dev. 1995, 9 (7), 769782,  DOI: 10.1101/gad.9.7.769
  322. 322
    Xiao, Q.; Castillo, S. O.; Nikodem, V. M. Distribution of Messenger RNAs for the Orphan Nuclear Receptors NURR1 and NUR77 (NGFI-B) in Adult Rat Brain Using in Situ Hybridization. Neuroscience 1996, 75 (1), 221230,  DOI: 10.1016/0306-4522(96)00159-5
  323. 323
    Zetterström, R. H.; Williams, R.; Perlmann, T.; Olson, L. Cellular Expression of the Immediate Early Transcription Factors Nurr1 and NGFI-B Suggests a Gene Regulatory Role in Several Brain Regions Including the Nigrostriatal Dopamine System. Mol. Brain Res. 1996, 41 (1–2), 111120,  DOI: 10.1016/0169-328X(96)00074-5
  324. 324
    Chao, L. C.; Wroblewski, K.; Zhang, Z.; Pei, L.; Vergnes, L.; Ilkayeva, O. R.; Ding, S. Y.; Reue, K.; Watt, M. J.; Newgard, C. B.; Pilch, P. F.; Hevener, A. L.; Tontonoz, P. Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77. Diabetes 2009, 58 (12), 27882796,  DOI: 10.2337/db09-0763
  325. 325
    Zhan, Y.; Chen, Y.; Zhang, Q.; Zhuang, J.; Tian, M.; Chen, H.; Zhang, L.; Zhang, H.; He, J.; Wang, W.; Wu, R.; Wang, Y.; Shi, C.; Yang, K.; Li, A.; Xin, Y.; Li, T. Y.; Yang, J. Y.; Zheng, Z.; Yu, C.; Lin, S.-C.; Chang, C.; Huang, P.; Lin, T.; Wu, Q. The Orphan Nuclear Receptor Nur77 Regulates LKB1 Localization and Activates AMPK. Nat. Chem. Biol. 2012, 8 (11), 897904,  DOI: 10.1038/nchembio.1069
  326. 326
    Kurakula, K.; Vos, M.; Logiantara, A.; Roelofs, J. J.; Nieuwenhuis, M. A.; Koppelman, G. H.; Postma, D. S.; van Rijt, L. S.; de Vries, C. J. M. Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-KB Activity in Lung Epithelial Cells. J. Immunol. 2015, 195 (4), 13881398,  DOI: 10.4049/jimmunol.1401714
  327. 327
    Hamers, A. A.J.; Vos, M.; Rassam, F.; Marinkovic, G.; Kurakula, K.; van Gorp, P. J.; de Winther, M. P.J.; Gijbels, M. J.J.; de Waard, V.; de Vries, C. J.M. Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis. Circ. Res. 2012, 110 (3), 428438,  DOI: 10.1161/CIRCRESAHA.111.260760
  328. 328
    Hanna, R. N.; Shaked, I.; Hubbeling, H. G.; Punt, J. A.; Wu, R.; Herrley, E.; Zaugg, C.; Pei, H.; Geissmann, F.; Ley, K.; Hedrick, C. C. NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis. Circ. Res. 2012, 110 (3), 416427,  DOI: 10.1161/CIRCRESAHA.111.253377
  329. 329
    De Silva, S.; Han, S.; Zhang, X.; Huston, D. P.; Winoto, A.; Zheng, B. Reduction of the Incidence and Severity of Collagen-Induced Arthritis by Constitutive Nur77 Expression in the T Cell Lineage. Arthritis Rheum. 2005, 52 (1), 333338,  DOI: 10.1002/art.20736
  330. 330
    Li, L.; Liu, Y.; Chen, H.; Li, F.; Wu, J.; Zhang, H.; He, J.; Xing, Y.; Chen, Y.; Wang, W.; Tian, X.; Li, A.; Zhang, Q.; Huang, P.; Han, J.; Lin, T.; Wu, Q. Impeding the Interaction between Nur77 and P38 Reduces LPS-Induced Inflammation. Nat. Chem. Biol. 2015, 11 (5), 339346,  DOI: 10.1038/nchembio.1788
  331. 331
    Beard, J. A.; Tenga, A.; Chen, T. The Interplay of NR4A Receptors and the Oncogene-Tumor Suppressor Networks in Cancer. Cell. Signalling 2015, 27 (2), 257266,  DOI: 10.1016/j.cellsig.2014.11.009
  332. 332
    Li, H.; Kolluri, S. K.; Gu, J.; Dawson, M. I.; Cao, X.; Hobbs, P. D.; Lin, B.; Chen, G.; Lu, J.; Lin, F.; Xie, Z.; Fontana, J. A.; Reed, J. C.; Zhang, X. Cytochrome c Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3. Science 2000, 289 (5482), 11591164,  DOI: 10.1126/science.289.5482.1159
  333. 333
    Cao, X.; Liu, W.; Lin, F.; Li, H.; Kolluri, S. K.; Lin, B.; Han, Y.; Dawson, M. I.; Zhang, X. Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting. Mol. Cell. Biol. 2004, 24 (22), 97059725,  DOI: 10.1128/MCB.24.22.9705-9725.2004
  334. 334
    Gilbert, F.; Morissette, M.; St-Hilaire, M.; Paquet, B.; Rouillard, C.; Di Paolo, T.; Lévesque, D. Nur77 Gene Knockout Alters Dopamine Neuron Biochemical Activity and Dopamine Turnover. Biol. Psychiatry 2006, 60 (6), 538547,  DOI: 10.1016/j.biopsych.2006.04.023
  335. 335
    Rouillard, C.; Baillargeon, J.; Paquet, B.; St-Hilaire, M.; Maheux, J.; Lévesque, C.; Darlix, N.; Majeur, S.; Lévesque, D. Genetic Disruption of the Nuclear Receptor Nur77 (Nr4a1) in Rat Reduces Dopamine Cell Loss and L-Dopa-Induced Dyskinesia in Experimental Parkinson’s Disease. Exp. Neurol. 2018, 304, 143153,  DOI: 10.1016/j.expneurol.2018.03.008
  336. 336
    Novak, G.; Gallo, A.; Zai, C. C.; Meltzer, H. Y.; Lieberman, J. A.; Potkin, S. G.; Voineskos, A. N.; Remington, G.; Kennedy, J. L.; Levesque, D.; Le Foll, B. Association of the Orphan Nuclear Receptor NR4A1 with Tardive Dyskinesia. Psychiatr. Genet. 2010, 20 (1), 3943,  DOI: 10.1097/YPG.0b013e3283351221
  337. 337
    St-Hilaire, M.; Bourhis, E.; Lévesque, D.; Rouillard, C. Impaired Behavioural and Molecular Adaptations to Dopamine Denervation and Repeated L-DOPA Treatment in Nur77-Knockout Mice. Eur. J. Neurosci. 2006, 24 (3), 795805,  DOI: 10.1111/j.1460-9568.2006.04954.x
  338. 338
    Éthier, I.; Beaudry, G.; St-Hilaire, M.; Milbrandt, J.; Rouillard, C.; Lévesque, D. The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression. Neuropsychopharmacology 2004, 29 (2), 335346,  DOI: 10.1038/sj.npp.1300318
  339. 339
    Mahmoudi, S.; Samadi, P.; Gilbert, F.; Ouattara, B.; Morissette, M.; Grégoire, L.; Rouillard, C.; Di Paolo, T.; Lévesque, D. Nur77 MRNA Levels and L-Dopa-Induced Dyskinesias in MPTP Monkeys Treated with Docosahexaenoic Acid. Neurobiol. Dis. 2009, 36 (1), 213222,  DOI: 10.1016/j.nbd.2009.07.017
  340. 340
    Mount, M. P.; Zhang, Y.; Amini, M.; Callaghan, S.; Kulczycki, J.; Mao, Z.; Slack, R. S.; Anisman, H.; Park, D. S. Perturbation of Transcription Factor Nur77 Expression Mediated by Myocyte Enhancer Factor 2D (MEF2D) Regulates Dopaminergic Neuron Loss in Response to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). J. Biol. Chem. 2013, 288 (20), 1436214371,  DOI: 10.1074/jbc.M112.439216
  341. 341
    Éthier, I.; Kagechika, H.; Shudo, K.; Rouillard, C.; Lévesque, D. Docosahexaenoic Acid Reduces Haloperidol-Induced Dyskinesias in Mice: Involvement of Nur77 and Retinoid Receptors. Biol. Psychiatry 2004, 56 (7), 522526,  DOI: 10.1016/j.biopsych.2004.06.036
  342. 342
    Wei, X.; Gao, H.; Zou, J.; Liu, X.; Chen, D.; Liao, J.; Xu, Y.; Ma, L.; Tang, B.; Zhang, Z.; Cai, X.; Jin, K.; Xia, Y.; Wang, Q. Contra-Directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-Inflammation and Anti-Mitochondrial Impairment. Mol. Neurobiol. 2016, 53 (9), 58765892,  DOI: 10.1007/s12035-015-9477-7
  343. 343
    Popichak, K. A.; Hammond, S. L.; Moreno, J. A.; Afzali, M. F.; Backos, D. S.; Slayden, R. D.; Safe, S.; Tjalkens, R. B. Compensatory Expression of NuR77 and NURR1 Regulates NF-KB–Dependent Inflammatory Signaling in Astrocytes. Mol. Pharmacol. 2018, 94 (4), 11741186,  DOI: 10.1124/mol.118.112631
  344. 344
    Liu, T.-Y.; Yang, X.-Y.; Zheng, L.-T.; Wang, G.-H.; Zhen, X.-C. Activation of Nur77 in Microglia Attenuates Proinflammatory Mediators Production and Protects Dopaminergic Neurons from Inflammation-Induced Cell Death. J. Neurochem. 2017, 140 (4), 589604,  DOI: 10.1111/jnc.13907
  345. 345
    Yan, J.; Huang, J.; Wu, J.; Fan, H.; Liu, A.; Qiao, L.; Shen, M.; Lai, X. Nur77 Attenuates Inflammatory Responses and Oxidative Stress by Inhibiting Phosphorylated IκB-α in Parkinson’s Disease Cell Model. Aging 2020, 12 (9), 81078119,  DOI: 10.18632/aging.103128
  346. 346
    Liebmann, M.; Hucke, S.; Koch, K.; Eschborn, M.; Ghelman, J.; Chasan, A. I.; Glander, S.; Schädlich, M.; Kuhlencord, M.; Daber, N. M.; Eveslage, M.; Beyer, M.; Dietrich, M.; Albrecht, P.; Stoll, M.; Busch, K. B.; Wiendl, H.; Roth, J.; Kuhlmann, T.; Klotz, L. Nur77 Serves as a Molecular Brake of the Metabolic Switch during T Cell Activation to Restrict Autoimmunity. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (34), E8017E8026,  DOI: 10.1073/pnas.1721049115
  347. 347
    Rothe, T.; Ipseiz, N.; Faas, M.; Lang, S.; Perez-Branguli, F.; Metzger, D.; Ichinose, H.; Winner, B.; Schett, G.; Krönke, G. The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation. J. Immunol. 2017, 198 (10), 38783885,  DOI: 10.4049/jimmunol.1600638
  348. 348
    Zhao, Y.; Liu, Y.; Zheng, D. Alpha 1-Antichymotrypsin/SerpinA3 Is a Novel Target of Orphan Nuclear Receptor Nur77. FEBS J. 2008, 275 (5), 10251038,  DOI: 10.1111/j.1742-4658.2008.06269.x
  349. 349
    Wang, L.; Zheng, Y.; Gao, X.; Liu, Y.; You, X. Retinoid X Receptor Ligand Regulates RXRα/Nur77-Dependent Apoptosis via Modulating Its Nuclear Export and Mitochondrial Targeting. Int. J. Clin. Exp. Pathol. 2017, 10 (11), 1077010780
  350. 350
    Zhan, Y.; Du, X.; Chen, H.; Liu, J.; Zhao, B.; Huang, D.; Li, G.; Xu, Q.; Zhang, M.; Weimer, B. C.; Chen, D.; Cheng, Z.; Zhang, L.; Li, Q.; Li, S.; Zheng, Z.; Song, S.; Huang, Y.; Ye, Z.; Su, W.; Lin, S.-C.; Shen, Y.; Wu, Q. Cytosporone B Is an Agonist for Nuclear Orphan Receptor Nur77. Nat. Chem. Biol. 2008, 4 (9), 548556,  DOI: 10.1038/nchembio.106
  351. 351
    Munoz-Tello, P.; Lin, H.; Khan, P.; De Vera, I. M. S.; Kamenecka, T. M.; Kojetin, D. J. Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1. J. Med. Chem. 2020, 63 (24), 1563915654,  DOI: 10.1021/acs.jmedchem.0c00894
  352. 352
    Liu, J.-J.; Zeng, H.-N.; Zhang, L.-R.; Zhan, Y.-Y.; Chen, Y.; Wang, Y.; Wang, J.; Xiang, S.-H.; Liu, W.-J.; Wang, W.-J.; Chen, H.-Z.; Shen, Y.-M.; Su, W.-J.; Huang, P.-Q.; Zhang, H.-K.; Wu, Q. A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In Vivo and In Vitro. Cancer Res. 2010, 70 (9), 36283637,  DOI: 10.1158/0008-5472.CAN-09-3160
  353. 353
    Yang, P.-B.; Hou, P.-P.; Liu, F.-Y.; Hong, W.-B.; Chen, H.-Z.; Sun, X.-Y.; Li, P.; Zhang, Y.; Ju, C.-Y.; Luo, L.-J.; Wu, S.-F.; Zhou, J.-X.; Wang, Z.-J.; He, J.-P.; Li, L.; Zhao, T.-J.; Deng, X.; Lin, T.; Wu, Q. Blocking PPARγ Interaction Facilitates Nur77 Interdiction of Fatty Acid Uptake and Suppresses Breast Cancer Progression. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (44), 2741227422,  DOI: 10.1073/pnas.2002997117
  354. 354
    Wang, W.; Wang, Y.; Chen, H.; Xing, Y.; Li, F.; Zhang, Q.; Zhou, B.; Zhang, H.; Zhang, J.; Bian, X.; Li, L.; Liu, Y.; Zhao, B.; Chen, Y.; Wu, R.; Li, A.; Yao, L.; Chen, P.; Zhang, Y.; Tian, X.; Beermann, F.; Wu, M.; Han, J.; Huang, P.; Lin, T.; Wu, Q. Orphan Nuclear Receptor TR3 Acts in Autophagic Cell Death via Mitochondrial Signaling Pathway. Nat. Chem. Biol. 2014, 10 (2), 133140,  DOI: 10.1038/nchembio.1406
  355. 355
    Wang, W.; Wang, Y.; Hou, P.-P.; Li, F.-W.; Zhou, B.; Chen, H.-Z.; Bian, X.-L.; Cai, Q.-X.; Xing, Y.-Z.; He, J.-P.; Zhang, H.; Huang, P.-Q.; Lin, T.; Wu, Q. Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity. Chem. Biol. 2015, 22 (8), 10401051,  DOI: 10.1016/j.chembiol.2015.06.023
  356. 356
    Hu, M.; Luo, Q.; Alitongbieke, G.; Chong, S.; Xu, C.; Xie, L.; Chen, X.; Zhang, D.; Zhou, Y.; Wang, Z.; Ye, X.; Cai, L.; Zhang, F.; Chen, H.; Jiang, F.; Fang, H.; Yang, S.; Liu, J.; Diaz-Meco, M. T.; Su, Y.; Zhou, H.; Moscat, J.; Lin, X.; Zhang, X.-K. Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy. Mol. Cell 2017, 66 (1), 141153,  DOI: 10.1016/j.molcel.2017.03.008
  357. 357
    Jung, Y.-S.; Lee, H.-S.; Cho, H.-R.; Kim, K.-J.; Kim, J.-H.; Safe, S.; Lee, S.-O. Dual Targeting of Nur77 and AMPKα by Isoalantolactone Inhibits Adipogenesis in Vitro and Decreases Body Fat Mass in Vivo. Int. J. Obes. 2019, 43 (5), 952962,  DOI: 10.1038/s41366-018-0276-x
  358. 358
    Vinayavekhin, N.; Saghatelian, A. Discovery of a Protein-Metabolite Interaction between Unsaturated Fatty Acids and the Nuclear Receptor Nur77 Using a Metabolomics Approach. J. Am. Chem. Soc. 2011, 133 (43), 1716817171,  DOI: 10.1021/ja208199h
  359. 359
    Lakshmi, S. P.; Reddy, A. T.; Banno, A.; Reddy, R. C. Molecular, Chemical, and Structural Characterization of Prostaglandin A2 as a Novel Agonist for Nur77. Biochem. J. 2019, 476 (19), 27572767,  DOI: 10.1042/BCJ20190253
  360. 360
    Willems, S.; Kilu, W.; Ni, X.; Chaikuad, A.; Knapp, S.; Heering, J.; Merk, D. The Orphan Nuclear Receptor Nurr1 Is Responsive to Non-Steroidal Anti-Inflammatory Drugs. Commun. Chem. 2020, 3 (1), 85,  DOI: 10.1038/s42004-020-0331-0
  361. 361
    Ordentlich, P.; Yan, Y.; Zhou, S.; Heyman, R. A. Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1. J. Biol. Chem. 2003, 278 (27), 2479124799,  DOI: 10.1074/jbc.M302167200
  362. 362
    Wansa, K. D. S. A.; Harris, J. M.; Yan, G.; Ordentlich, P.; Muscat, G. E. O. The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-Activation, Coactivator Recruitment, and Activation by the Purine Anti-Metabolite 6-Mercaptopurine. J. Biol. Chem. 2003, 278 (27), 2477624790,  DOI: 10.1074/jbc.M300088200
  363. 363
    Yoo, Y. G.; Na, T. Y.; Yang, W. K.; Kim, H. J.; Lee, I. K.; Kong, G.; Chung, J. H.; Lee, M. O. 6-Mercaptopurine, an Activator of Nur77, Enhances Transcriptional Activity of HIF-1α Resulting in New Vessel Formation. Oncogene 2007, 26 (26), 38233834,  DOI: 10.1038/sj.onc.1210149
  364. 364
    Lee, H.-S.; Safe, S.; Lee, S.-O. Inactivation of the Orphan Nuclear Receptor NR4A1 Contributes to Apoptosis Induction by Fangchinoline in Pancreatic Cancer Cells. Toxicol. Appl. Pharmacol. 2017, 332, 3239,  DOI: 10.1016/j.taap.2017.07.017
  365. 365
    Lee, S.-O.; Li, X.; Hedrick, E.; Jin, U.-H.; Tjalkens, R. B.; Backos, D. S.; Li, L.; Zhang, Y.; Wu, Q.; Safe, S. Diindolylmethane Analogs Bind NR4A1 and Are NR4A1 Antagonists in Colon Cancer Cells. Mol. Endocrinol. 2014, 28 (10), 17291739,  DOI: 10.1210/me.2014-1102
  366. 366
    Lee, S. O.; Abdelrahim, M.; Yoon, K.; Chintharlapalli, S.; Papineni, S.; Kim, K.; Wang, H.; Safe, S. Inactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor Growth. Cancer Res. 2010, 70 (17), 68246836,  DOI: 10.1158/0008-5472.CAN-10-1992
  367. 367
    Yoon, K.; Lee, S.-O.; Cho, S.-D.; Kim, K.; Khan, S.; Safe, S. Activation of Nuclear TR3 (NR4A1) by a Diindolylmethane Analog Induces Apoptosis and Proapoptotic Genes in Pancreatic Cancer Cells and Tumors. Carcinogenesis 2011, 32 (6), 836842,  DOI: 10.1093/carcin/bgr040
  368. 368
    Liu, J.; Wang, G.-H.; Duan, Y.-H.; Dai, Y.; Bao, Y.; Hu, M.; Zhou, Y.-Q.; Li, M.; Jiang, F.; Zhou, H.; Yao, X.-S.; Zhang, X.-K. Modulation of the Nur77-Bcl-2 Apoptotic Pathway by P38α MAPK. Oncotarget 2017, 8 (41), 6973169745,  DOI: 10.18632/oncotarget.19227
  369. 369
    Yao, L.-M.; He, J.-P.; Chen, H.-Z.; Wang, Y.; Wang, W.-J.; Wu, R.; Yu, C.-D.; Wu, Q. Orphan Receptor TR3 Participates in Cisplatin-Induced Apoptosis via Chk2 Phosphorylation to Repress Intestinal Tumorigenesis. Carcinogenesis 2012, 33 (2), 301311,  DOI: 10.1093/carcin/bgr287
  370. 370
    Qi, H.; Jiang, Z.; Wang, C.; Yang, Y.; Li, L.; He, H.; Yu, Z. Sensitization of Tamoxifen-Resistant Breast Cancer Cells by Z-Ligustilide through Inhibiting Autophagy and Accumulating DNA Damages. Oncotarget 2017, 8 (17), 2930029317,  DOI: 10.18632/oncotarget.16832
  371. 371
    Codina, A.; Benoit, G.; Gooch, J. T.; Neuhaus, D.; Perlmann, T.; Schwabe, J. W. R. Identification of a Novel Co-Regulator Interaction Surface on the Ligand Binding Domain of Nurr1 Using NMR Footprinting. J. Biol. Chem. 2004, 279 (51), 5333853345,  DOI: 10.1074/jbc.M409096200
  372. 372
    Volakakis, N.; Malewicz, M.; Kadkhodai, B.; Perlmann, T.; Benoit, G. Characterization of the Nurr1 Ligand-Binding Domin Co-Activator Interaction Surface. J. Mol. Endocrinol. 2006, 37 (2), 317326,  DOI: 10.1677/jme.1.02106
  373. 373
    Galleguillos, D.; Vecchiola, A.; Fuentealba, J. A.; Ojeda, V.; Alvarez, K.; Gómez, A.; Andrés, M. E. PIASγ Represses the Transcriptional Activation Induced by the Nuclear Receptor Nurr1. J. Biol. Chem. 2004, 279 (3), 20052011,  DOI: 10.1074/jbc.M308113200
  374. 374
    Zetterström, R. H.; Solomin, L.; Jansson, L.; Hoffer, B. J.; Olson, L.; Perlmann, T. Dopamine Neuron Agenesis in Nurr1-Deficient Mice. Science 1997, 276 (5310), 248250,  DOI: 10.1126/science.276.5310.248
  375. 375
    Wallén, Å.; Zetterström, R. H.; Solomin, L.; Arvidsson, M.; Olson, L.; Perlmann, T. Fate of Mesencephalic AHD2-Expressing Dopamine Progenitor Cells in Nurr1Mutant Mice. Exp. Cell Res. 1999, 253 (2), 737746,  DOI: 10.1006/excr.1999.4691
  376. 376
    Smits, S. M.; Ponnio, T.; Conneely, O. M.; Burbach, J. P. H.; Smidt, M. P. Involvement of Nurr1 in Specifying the Neurotransmitter Identity of Ventral Midbrain Dopaminergic Neurons. Eur. J. Neurosci. 2003, 18 (7), 17311738,  DOI: 10.1046/j.1460-9568.2003.02885.x
  377. 377
    Hermanson, E.; Joseph, B.; Castro, D.; Lindqvist, E.; Aarnisalo, P.; Wallén, Å.; Benoit, G.; Hengerer, B.; Olson, L.; Perlmann, T. Nurr1 Regulates Dopamine Synthesis and Storage in MN9D Dopamine Cells. Exp. Cell Res. 2003, 288 (2), 324334,  DOI: 10.1016/S0014-4827(03)00216-7
  378. 378
    Jacobs, F. M. J.; van der Linden, A. J. A.; Wang, Y.; von Oerthel, L.; Sul, H. S.; Burbach, J. P. H.; Smidt, M. P. Identification of Dlk1, Ptpru and Klhl1 as Novel Nurr1 Target Genes in Meso-Diencephalic Dopamine Neurons. Development 2009, 136 (14), 23632373,  DOI: 10.1242/dev.037556
  379. 379
    Gil, M.; McKinney, C.; Lee, M. K.; Eells, J. B.; Phyillaier, M. A.; Nikodem, V. M. Regulation of GTP Cyclohydrolase I Expression by Orphan Receptor Nurr1 in Cell Culture and in Vivo. J. Neurochem. 2007, 101 (1), 142150,  DOI: 10.1111/j.1471-4159.2006.04356.x
  380. 380
    Luo, Y.; Henricksen, L. A.; Giuliano, R. E.; Prifti, L.; Callahan, L. M.; Federoff, H. J. VIP Is a Transcriptional Target of Nurr1 in Dopaminergic Cells. Exp. Neurol. 2007, 203 (1), 221232,  DOI: 10.1016/j.expneurol.2006.08.005
  381. 381
    Wallén, Å.; Castro, D. S.; Zetterström, R. H.; Karlén, M.; Olson, L.; Ericson, J.; Perlmann, T. Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain Stem. Mol. Cell. Neurosci. 2001, 18 (6), 649663,  DOI: 10.1006/mcne.2001.1057
  382. 382
    Heng, X.; Jin, G.; Zhang, X.; Yang, D.; Zhu, M.; Fu, S.; Li, X.; Le, W. Nurr1 Regulates Top IIβ and Functions in Axon Genesis of Mesencephalic Dopaminergic Neurons. Mol. Neurodegener. 2012, 7 (1), 4,  DOI: 10.1186/1750-1326-7-4
  383. 383
    Montarolo, F.; Martire, S.; Perga, S.; Spadaro, M.; Brescia, I.; Allegra, S.; De Francia, S.; Bertolotto, A. NURR1 Deficiency Is Associated to ADHD-like Phenotypes in Mice. Transl. Psychiatry 2019, 9 (1), 207,  DOI: 10.1038/s41398-019-0544-0
  384. 384
    McCoy, J. M.; Walkenhorst, D. E.; McCauley, K. S.; Elaasar, H.; Everett, J. R.; Mix, K. S. Orphan Nuclear Receptor NR4A2 Induces Transcription of the Immunomodulatory Peptide Hormone Prolactin. J. Inflammation 2015, 12, 13,  DOI: 10.1186/s12950-015-0059-2
  385. 385
    Safe, S.; Jin, U. H.; Morpurgo, B.; Abudayyeh, A.; Singh, M.; Tjalkens, R. B. Nuclear Receptor 4A (NR4A) Family - Orphans No More. J. Steroid Biochem. Mol. Biol. 2016, 157, 4860,  DOI: 10.1016/j.jsbmb.2015.04.016
  386. 386
    Decressac, M.; Volakakis, N.; Björklund, A.; Perlmann, T. NURR1 in Parkinson Disease - From Pathogenesis to Therapeutic Potential. Nat. Rev. Neurol. 2013, 9 (11), 629636,  DOI: 10.1038/nrneurol.2013.209
  387. 387
    Liu, H.; Liu, H.; Li, T.; Cui, J.; Fu, Y.; Ren, J.; Sun, X.; Jiang, P.; Yu, S.; Li, C. NR4A2 Genetic Variation and Parkinson’s Disease: Evidence from a Systematic Review and Meta-Analysis. Neurosci. Lett. 2017, 650, 2532,  DOI: 10.1016/j.neulet.2017.01.062
  388. 388
    Chu, Y.; Le, W.; Kompoliti, K.; Jankovic, J.; Mufson, E. J.; Kordower, J. H. Nurr1 in Parkinson’s Disease and Related Disorders. J. Comp. Neurol. 2006, 494 (3), 495514,  DOI: 10.1002/cne.20828
  389. 389
    Decressac, M.; Kadkhodaei, B.; Mattsson, B.; Laguna, A.; Perlmann, T.; Björklund, A. α-Synuclein-Induced down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons. Sci. Transl. Med. 2012, 4 (163), 163ra156,  DOI: 10.1126/scitranslmed.3004676
  390. 390
    Liu, W.; Gao, Y.; Chang, N. Nurr1 Overexpression Exerts Neuroprotective and Anti-Inflammatory Roles via down-Regulating CCL2 Expression in Both in Vivo and in Vitro Parkinson’s Disease Models. Biochem. Biophys. Res. Commun. 2017, 482 (4), 13121319,  DOI: 10.1016/j.bbrc.2016.12.034
  391. 391
    Volakakis, N.; Tiklova, K.; Decressac, M.; Papathanou, M.; Mattsson, B.; Gillberg, L.; Nobre, A.; Björklund, A.; Perlmann, T. Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. J. Neurosci. 2015, 35 (42), 1437014385,  DOI: 10.1523/JNEUROSCI.1155-15.2015
  392. 392
    Volakakis, N.; Kadkhodaei, B.; Joodmardi, E.; Wallis, K.; Panman, L.; Silvaggi, J.; Spiegelman, B. M.; Perlmann, T. NR4A Orphan Nuclear Receptors as Mediators of CREB-Dependent Neuroprotection. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (27), 1231712322,  DOI: 10.1073/pnas.1007088107
  393. 393
    Wang, X.; Zhuang, W.; Fu, W.; Wang, X.; Lv, E.; Li, F.; Zhou, S.; Rausch, W.-D.; Wang, X. The Lentiviral-Mediated Nurr1 Genetic Engineering Mesenchymal Stem Cells Protect Dopaminergic Neurons in a Rat Model of Parkinson’s Disease. Am. J. Transl. Res. 2018, 10 (6), 15831599
  394. 394
    Saijo, K.; Winner, B.; Carson, C. T.; Collier, J. G.; Boyer, L.; Rosenfeld, M. G.; Gage, F. H.; Glass, C. K. A Nurr1/CoREST Pathway in Microglia and Astrocytes Protects Dopaminergic Neurons from Inflammation-Induced Death. Cell 2009, 137 (1), 4759,  DOI: 10.1016/j.cell.2009.01.038
  395. 395
    Yi, S.-H.; He, X.-B.; Rhee, Y.-H.; Park, C.-H.; Takizawa, T.; Nakashima, K.; Lee, S.-H. Foxa2 Acts as a Co-Activator Potentiating Expression of the Nurr1-Induced DA Phenotype via Epigenetic Regulation. Development 2014, 141 (4), 761772,  DOI: 10.1242/dev.095802
  396. 396
    Kim, C.-H.; Han, B.-S.; Moon, J.; Kim, D.-J.; Shin, J.; Rajan, S.; Nguyen, Q. T.; Sohn, M.; Kim, W.-G.; Han, M.; Jeong, I.; Kim, K.-S.; Lee, E.-H.; Tu, Y.; Naffin-Olivos, J. L.; Park, C.-H.; Ringe, D.; Yoon, H. S.; Petsko, G. A.; Kim, K.-S. Nuclear Receptor Nurr1 Agonists Enhance Its Dual Functions and Improve Behavioral Deficits in an Animal Model of Parkinson’s Disease. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (28), 87568761,  DOI: 10.1073/pnas.1509742112
  397. 397
    Rajan, S.; Jang, Y.; Kim, C.-H.; Kim, W.; Toh, H. T.; Jeon, J.; Song, B.; Serra, A.; Lescar, J.; Yoo, J. Y.; Beldar, S.; Ye, H.; Kang, C.; Liu, X.-W.; Feitosa, M.; Kim, Y.; Hwang, D.; Goh, G.; Lim, K.-L.; Park, H. M.; Lee, C. H.; Oh, S. F.; Petsko, G. A.; Yoon, H. S.; Kim, K.-S. PGE1 and PGA1 Bind to Nurr1 and Activate Its Transcriptional Function. Nat. Chem. Biol. 2020, 16, 876886,  DOI: 10.1038/s41589-020-0553-6
  398. 398
    Bruning, J. M.; Wang, Y.; Oltrabella, F.; Tian, B.; Kholodar, S. A.; Liu, H.; Bhattacharya, P.; Guo, S.; Holton, J. M.; Fletterick, R. J.; Jacobson, M. P.; England, P. M. Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell Chem. Biol. 2019, 26 (5), 674685,  DOI: 10.1016/j.chembiol.2019.02.002
  399. 399
    Smith, G. A.; Rocha, E. M.; Rooney, T.; Barneoud, P.; McLean, J. R.; Beagan, J.; Osborn, T.; Coimbra, M.; Luo, Y.; Hallett, P. J.; Isacson, O. A Nurr1 Agonist Causes Neuroprotection in a Parkinson’s Disease Lesion Model Primed with the Toll-Like Receptor 3 DsRNA Inflammatory Stimulant Poly(I:C). PLoS One 2015, 10 (3), e0121072,  DOI: 10.1371/journal.pone.0121072
  400. 400
    Zhang, Z.; Li, X.; Xie, W.; Tuo, H.; Hintermann, S.; Jankovic, J.; Le, W. Anti-Parkinsonian Effects of Nurr1 Activator in Ubiquitin-Proteasome System Impairment Induced Animal Model of Parkinson’s Disease. CNS Neurol. Disord.: Drug Targets 2012, 11 (6), 768773,  DOI: 10.2174/187152712803581155
  401. 401
    Friling, S.; Bergsland, M.; Kjellander, S. Activation of Retinoid X Receptor Increases Dopamine Cell Survival in Models for Parkinson’s Disease. BMC Neurosci. 2009, 10, 146,  DOI: 10.1186/1471-2202-10-146
  402. 402
    Spathis, A. D.; Asvos, X.; Ziavra, D.; Karampelas, T.; Topouzis, S.; Cournia, Z.; Qing, X.; Alexakos, P.; Smits, L. M.; Dalla, C.; Rideout, H. J.; Schwamborn, J. C.; Tamvakopoulos, C.; Fokas, D.; Vassilatis, D. K. Nurr1:RXRα Heterodimer Activation as Monotherapy for Parkinson’s Disease. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (15), 39994004,  DOI: 10.1073/pnas.1616874114
  403. 403
    Wang, J.; Bi, W.; Zhao, W.; Varghese, M.; Koch, R. J.; Walker, R. H.; Chandraratna, R. A.; Sanders, M. E.; Janesick, A.; Blumberg, B.; Ward, L.; Ho, L.; Pasinetti, G. M. Selective Brain Penetrable Nurr1 Transactivator for Treating Parkinson’s Disease. Oncotarget 2016, 7 (7), 74697479,  DOI: 10.18632/oncotarget.7191
  404. 404
    Loppi, S.; Kolosowska, N.; Kärkkäinen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T. HX600, a Synthetic Agonist for RXR-Nurr1 Heterodimer Complex, Prevents Ischemia-Induced Neuronal Damage. Brain, Behav., Immun. 2018, 73, 670681,  DOI: 10.1016/j.bbi.2018.07.021
  405. 405
    Jeon, S. G.; Yoo, A.; Chun, D. W.; Hong, S. B.; Chung, H.; Kim, J.-I.; Moon, M. The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-Related Pathogenesis. Aging Dis. 2020, 11 (3), 705724,  DOI: 10.14336/AD.2019.0718
  406. 406
    Terzioglu-Usak, S.; Negis, Y.; Karabulut, D. S.; Zaim, M.; Isik, S. Cellular Model of Alzheimer’s Disease: Aβ1–42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 Expression. Curr. Alzheimer Res. 2017, 14 (6), 636644,  DOI: 10.2174/1567205014666170117103217
  407. 407
    Parra-Damas, A.; Valero, J.; Chen, M.; España, J.; Martín, E.; Ferrer, I.; Rodríguez-Alvarez, J.; Saura, C. A. Crtc1 Activates a Transcriptional Program Deregulated at Early Alzheimer’s Disease-Related Stages. J. Neurosci. 2014, 34 (17), 57765787,  DOI: 10.1523/JNEUROSCI.5288-13.2014
  408. 408
    Moon, M.; Jeong, I.; Kim, C.-H.; Kim, J.; Lee, P. K. J.; Mook-Jung, I.; Leblanc, P.; Kim, K.-S. Correlation between Orphan Nuclear Receptor Nurr1 Expression and Amyloid Deposition in 5XFAD Mice, an Animal Model of Alzheimer’s Disease. J. Neurochem. 2015, 132 (2), 254262,  DOI: 10.1111/jnc.12935
  409. 409
    Moon, M.; Jung, E. S.; Jeon, S. G.; Cha, M.-Y.; Jang, Y.; Kim, W.; Lopes, C.; Mook-Jung, I.; Kim, K.-S. Nurr1 (NR4A2) Regulates Alzheimer’s Disease-Related Pathogenesis and Cognitive Function in the 5XFAD Mouse Model. Aging Cell 2019, 18 (1), e12866,  DOI: 10.1111/acel.12866
  410. 410
    Montarolo, F.; Raffaele, C.; Perga, S.; Martire, S.; Finardi, A.; Furlan, R.; Hintermann, S.; Bertolotto, A. Effects of Isoxazolo-Pyridinone 7e, a Potent Activator of the Nurr1 Signaling Pathway, on Experimental Autoimmune Encephalomyelitis in Mice. PLoS One 2014, 9 (9), e108791,  DOI: 10.1371/journal.pone.0108791
  411. 411
    Montarolo, F.; Perga, S.; Martire, S.; Bertolotto, A. Nurr1 Reduction Influences the Onset of Chronic EAE in Mice. Inflammation Res. 2015, 64 (11), 841844,  DOI: 10.1007/s00011-015-0871-4
  412. 412
    Raveney, B. J. E.; Oki, S.; Yamamura, T. Nuclear Receptor NR4A2 Orchestrates Th17 Cell-Mediated Autoimmune Inflammation via IL-21 Signalling. PLoS One 2013, 8 (2), e56595,  DOI: 10.1371/journal.pone.0056595
  413. 413
    Park, T.-Y.; Jang, Y.; Kim, W.; Shin, J.; Toh, H. T.; Kim, C.-H.; Yoon, H. S.; Leblanc, P.; Kim, K.-S. Chloroquine Modulates Inflammatory Autoimmune Responses through Nurr1 in Autoimmune Diseases. Sci. Rep. 2019, 9, 15559,  DOI: 10.1038/s41598-019-52085-w
  414. 414
    Willems, S.; Ohrndorf, J.; Kilu, W.; Heering, J.; Merk, D. Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation Mechanisms. J. Med. Chem. 2021, 64 (5), 26592668,  DOI: 10.1021/acs.jmedchem.0c01779
  415. 415
    de Vera, I. M. S.; Giri, P. K.; Munoz-Tello, P.; Brust, R.; Fuhrmann, J.; Matta-Camacho, E.; Shang, J.; Campbell, S.; Wilson, H. D.; Granados, J.; Gardner, W. J. J.; Creamer, T. P.; Solt, L. A.; Kojetin, D. J. Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1. ACS Chem. Biol. 2016, 11 (7), 17951799,  DOI: 10.1021/acschembio.6b00037
  416. 416
    de Vera, I. M. S.; Munoz-Tello, P.; Zheng, J.; Dharmarajan, V.; Marciano, D. P.; Matta-Camacho, E.; Giri, P. K.; Shang, J.; Hughes, T. S.; Rance, M.; Griffin, P. R.; Kojetin, D. J. Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. Structure 2019, 27 (1), 6677,  DOI: 10.1016/j.str.2018.10.002
  417. 417
    Windshügel, B. Structural Insights into Ligand-Binding Pocket Formation in Nurr1 by Molecular Dynamics Simulations. J. Biomol. Struct. Dyn. 2019, 37 (17), 46514657,  DOI: 10.1080/07391102.2018.1559099
  418. 418
    Lesuisse, D.; Malanda, A.; Peyronel, J. F.; Evanno, Y.; Lardenois, P.; De-Peretti, D.; Abécassis, P.-Y.; Barnéoud, P.; Brunel, P.; Burgevin, M.-C.; Cegarra, C.; Auger, F.; Dommergue, A.; Lafon, C.; Even, L.; Tsi, J.; Luc, T. P. H.; Almario, A.; Olivier, A.; Castel, M.-N.; Taupin, V.; Rooney, T.; Vigé, X. Development of a Novel NURR1/NOT Agonist from Hit to Lead and Candidate for the Potential Treatment of Parkinson’s Disease. Bioorg. Med. Chem. Lett. 2019, 29 (7), 929932,  DOI: 10.1016/j.bmcl.2019.01.024
  419. 419
    Almario Garcia, A.; Lardenois, P.; Olivier, A. Derivatives of 2-Aryl-6-Phenyl-Imid Azo [1, 2-α]Pyridines, Their Preparation and Their Therapeutic Use. WO2008/034974A1. Sanofi-Aventis, 2008.
  420. 420
    Malanda, A.; Abécassis, P.-Y.; Barnéoud, P.; Brunel, P.; Taupin, V.; Vigé, X.; Lesuisse, D. Data on Synthesis, ADME and Pharmacological Properties and Early Safety Pharmacology Evaluation of a Series of Novel NURR1/NOT Agonist Potentially Useful for the Treatment of Parkinson’s Disease. Data Br. 2019, 27, 104057,  DOI: 10.1016/j.dib.2019.104057
  421. 421
    Dubois, C.; Hengerer, B.; Mattes, H. Identification of a Potent Agonist of the Orphan Nuclear Receptor Nurr1. ChemMedChem 2006, 1 (9), 955958,  DOI: 10.1002/cmdc.200600078
  422. 422
    Hintermann, S.; Chiesi, M.; von Krosigk, U.; Mathé, D.; Felber, R.; Hengerer, B. Identification of a Series of Highly Potent Activators of the Nurr1 Signaling Pathway. Bioorg. Med. Chem. Lett. 2007, 17 (1), 193196,  DOI: 10.1016/j.bmcl.2006.09.062
  423. 423
    Li, X.; Lee, S.-O.; Safe, S. Structure-Dependent Activation of NR4A2 (Nurr1) by 1,1-Bis(3′- Indolyl)-1-(Aromatic)Methane Analogs in Pancreatic Cancer Cells. Biochem. Pharmacol. 2012, 83 (10), 14451455,  DOI: 10.1016/j.bcp.2012.02.021
  424. 424
    Inamoto, T.; Papineni, S.; Chintharlapalli, S.; Cho, S. D.; Safe, S.; Kamat, A. M. 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Activates the Orphan Nuclear Receptor Nurr1 and Inhibits Bladder Cancer Growth. Mol. Cancer Ther. 2008, 7 (12), 38253833,  DOI: 10.1158/1535-7163.MCT-08-0730
  425. 425
    De Miranda, B. R.; Popichak, K. A.; Hammond, S. L.; Miller, J. A.; Safe, S.; Tjalkens, R. B. Novel Para-Phenyl Substituted Diindolylmethanes Protect against MPTP Neurotoxicity and Suppress Glial Activation in a Mouse Model of Parkinson’s Disease. Toxicol. Sci. 2015, 143 (2), 360373,  DOI: 10.1093/toxsci/kfu236
  426. 426
    Hammond, S. L.; Safe, S.; Tjalkens, R. B. A Novel Synthetic Activator of Nurr1 Induces Dopaminergic Gene Expression and Protects against 6-Hydroxydopamine Neurotoxicity in Vitro. Neurosci. Lett. 2015, 607, 8389,  DOI: 10.1016/j.neulet.2015.09.015
  427. 427
    Hammond, S. L.; Tjalkens, R. B.; Safe, S.; Richman, E. H.; Backos, D. S.; Li, X.; Hunt, L. G.; Chong, E.; Popichak, K. A.; Damale, P. The Nurr1 Ligand,1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism. J. Pharmacol. Exp. Ther. 2018, 365 (3), 636651,  DOI: 10.1124/jpet.117.246389
  428. 428
    Karki, K.; Li, X.; Jin, U.-H.; Mohankumar, K.; Zarei, M.; Michelhaugh, S. K.; Mittal, S.; Tjalkens, R.; Safe, S. Nuclear Receptor 4A2 (NR4A2) Is a Druggable Target for Glioblastomas. J. Neuro-Oncol. 2020, 146 (1), 2539,  DOI: 10.1007/s11060-019-03349-y
  429. 429
    De Miranda, B. R.; Miller, J. A.; Hansen, R. J.; Lunghofer, P. J.; Safe, S.; Gustafson, D. L.; Colagiovanni, D.; Tjalkens, R. B. Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-Inflammatory Para-Phenyl Substituted Diindolylmethanes in a Mouse Mdel of Parkinson’s Disease. J. Pharmacol. Exp. Ther. 2013, 345 (1), 125138,  DOI: 10.1124/jpet.112.201558
  430. 430
    Hibino, S.; Chikuma, S.; Kondo, T.; Ito, M.; Nakatsukasa, H.; Omata-Mise, S.; Yoshimura, A. Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance. Cancer Res. 2018, 78 (11), 30273040,  DOI: 10.1158/0008-5472.CAN-17-3102
  431. 431
    Komiya, T.; Yamamoto, S.; Roy, A.; McDonald, P.; Perez, R. P. Drug Screening to Target Nuclear Orphan Receptor NR4A2 for Cancer Therapeutics. Transl. Lung Cancer Res. 2017, 6 (5), 600610,  DOI: 10.21037/tlcr.2017.07.02
  432. 432
    Pan, T.; Xie, W.; Jankovic, J.; Le, W. Biological Effects of Pramipexole on Dopaminergic Neuron-Associated Genes: Relevance to Neuroprotection. Neurosci. Lett. 2005, 377 (2), 106109,  DOI: 10.1016/j.neulet.2004.11.080
  433. 433
    Hedya, S. A.; Safar, M. M.; Bahgat, A. K. Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model. Mol. Neurobiol. 2018, 55 (9), 75797587,  DOI: 10.1007/s12035-018-0923-1
  434. 434
    Ham, A.; Lee, H. J.; Hong, S. S.; Lee, D.; Mar, W. Moracenin D from Mori Cortex Radicis Protects SH-SY5Y Cells against Dopamine-Induced Cell Death by Regulating Nurr1 and α-Synuclein Expression. Phytother. Res. 2012, 26 (4), 620624,  DOI: 10.1002/ptr.3592
  435. 435
    Wallén-Mackenzie, Å.; De Urquiza, A. M.; Petersson, S.; Rodriguez, F. J.; Friling, S.; Wagner, J.; Ordentlich, P.; Lengqvist, J.; Heyman, R. A.; Arenas, E.; Perlmann, T. Nurr1-RXR Heterodimers Mediate RXR Ligand-Induced Signaling in Neuronal Cells. Genes Dev. 2003, 17 (24), 30363047,  DOI: 10.1101/gad.276003
  436. 436
    Morita, K.; Kawana, K.; Sodeyama, M.; Shimomura, I.; Kagechika, H.; Makishima, M. Selective Allosteric Ligand Activation of the Retinoid X Receptor Heterodimers of NGFI-B and Nurr1. Biochem. Pharmacol. 2005, 71 (1–2), 98107,  DOI: 10.1016/j.bcp.2005.10.017
  437. 437
    Ishizawa, M.; Kagechika, H.; Makishima, M. NR4A Nuclear Receptors Mediate Carnitine Palmitoyltransferase 1A Gene Expression by the Rexinoid HX600. Biochem. Biophys. Res. Commun. 2012, 418 (4), 780785,  DOI: 10.1016/j.bbrc.2012.01.102
  438. 438
    Sundén, H.; Schäfer, A.; Scheepstra, M.; Leysen, S.; Malo, M.; Ma, J.-N.; Burstein, E. S.; Ottmann, C.; Brunsveld, L.; Olsson, R. Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation. J. Med. Chem. 2016, 59 (3), 12321238,  DOI: 10.1021/acs.jmedchem.5b01702
  439. 439
    Scheepstra, M.; Andrei, S. A.; de Vries, R. M. J. M.; Meijer, F. A.; Ma, J.-N.; Burstein, E. S.; Olsson, R.; Ottmann, C.; Milroy, L.-G.; Brunsveld, L. Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. ACS Chem. Neurosci. 2017, 8 (9), 20652077,  DOI: 10.1021/acschemneuro.7b00216
  440. 440
    McFarland, K.; Spalding, T. A.; Hubbard, D.; Ma, J.-N.; Olsson, R.; Burstein, E. S. Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson’s Disease. ACS Chem. Neurosci. 2013, 4 (11), 14301438,  DOI: 10.1021/cn400100f
  441. 441
    Pönniö, T.; Conneely, O. M. Nor-1 Regulates Hippocampal Axon Guidance, Pyramidal Cell Survival, and Seizure Susceptibility. Mol. Cell. Biol. 2004, 24 (20), 90709078,  DOI: 10.1128/MCB.24.20.9070-9078.2004
  442. 442
    Ferrán, B.; Martí-Pàmies, I.; Alonso, J.; Rodríguez-calvo, R.; Aguiló, S.; Vidal, F.; Rodríguez, C.; Martínez-gonzález, J. The Nuclear Receptor NOR-1 Regulates the Small Muscle Protein, X-Linked (SMPX) and Myotube Differentiation. Sci. Rep. 2016, 6, 25944,  DOI: 10.1038/srep25944
  443. 443
    Kon, T.; Miki, Y.; Tanji, K.; Mori, F.; Tomiyama, M.; Toyoshima, Y.; Kakita, A.; Takahashi, H.; Utsumi, J.; Sasaki, H.; Wakabayashi, K. Localization of Nuclear Receptor Subfamily 4, Group A, Member 3 (NR4A3) in Lewy Body Disease and Multiple System Atrophy. Neuropathology 2015, 35 (6), 503509,  DOI: 10.1111/neup.12210
  444. 444
    Maheux, J.; Ethier, I.; Rouillard, C.; Levesque, D. Induction Patterns of Transcription Factors of the Nur Family (Nurr1, Nur77, and Nor −1) by Typical and Atypical Antipsychotics in the Mouse Brain : Implication for Their Mechanism of Action. J. Pharmacol. Exp. Ther. 2005, 313 (1), 460473,  DOI: 10.1124/jpet.104.080184
  445. 445
    DeYoung, R. A.; Baker, J. C.; Cado, D.; Winoto, A. The Orphan Steroid Receptor Nur77 Family Member Nor-1 Is Essential for Early Mouse Embryogenesis. J. Biol. Chem. 2003, 278 (47), 4710447109,  DOI: 10.1074/jbc.M307496200
  446. 446
    Chio, C.-C.; Wei, L.; Chen, T. G.; Lin, C.-M.; Shieh, J.-P.; Yeh, P.-S.; Chen, R.-M. Neuron-Derived Orphan Receptor 1 Transduces Survival Signals in Neuronal Cells in Response to Hypoxia-Induced Apoptotic Insults. J. Neurosurg. 2016, 124 (6), 16541664,  DOI: 10.3171/2015.6.JNS1535
  447. 447
    Kagaya, S.; Ohkura, N.; Tsukada, T.; Miyagawa, M.; Sugita, Y.; Tsujimoto, G.; Matsumoto, K.; Saito, H.; Hashida, R. Prostaglandin A 2 Acts as a Transactivator for NOR1 (NR4A3) within the Nuclear Receptor Superfamily. Biol. Pharm. Bull. 2005, 28 (9), 16031607,  DOI: 10.1248/bpb.28.1603
  448. 448
    Eyster, K. M. The Estrogen Receptors: An Overview from Different Perspectives. In Methods in Molecular Biology; Humana Press Inc., 2016; Vol. 1366, pp 110.
  449. 449
    Dahlman-Wright, K.; Cavailles, V.; Fuqua, S. A.; Jordan, V. C.; Katzenellenbogen, J. A.; Korach, K. S.; Maggi, A.; Muramatsu, M.; Parker, M. G.; Gustafsson, J.-Å. International Union of Pharmacology. LXIV. Estrogen Receptors. Pharmacol. Rev. 2006, 58 (4), 773781,  DOI: 10.1124/pr.58.4.8
  450. 450
    Hewitt, S. C.; Korach, K. S. Estrogen Receptors: New Directions in the New Millennium. Endocr. Rev. 2018, 39 (5), 664675,  DOI: 10.1210/er.2018-00087
  451. 451
    Dupont, S.; Krust, A.; Gansmuller, A.; Dierich, A.; Chambon, P.; Mark, M. Effect of Single and Compound Knockouts of Estrogen Receptors Alpha (ERalpha) and Beta (ERbeta) on Mouse Reproductive Phenotypes. Development 2000, 127 (19), 42774291,  DOI: 10.1242/dev.127.19.4277
  452. 452
    Lan, Y.-L.; Zhao, J.; Li, S. Update on the Neuroprotective Effect of Estrogen Receptor Alpha Against Alzheimer’s Disease. J. Alzheimer's Dis. 2015, 43 (4), 11371148,  DOI: 10.3233/JAD-141875
  453. 453
    Chakrabarti, M.; Haque, A.; Banik, N. L.; Nagarkatti, P.; Nagarkatti, M.; Ray, S. K. Estrogen Receptor Agonists for Attenuation of Neuroinflammation and Neurodegeneration. Brain Res. Bull. 2014, 109, 2231,  DOI: 10.1016/j.brainresbull.2014.09.004
  454. 454
    Pike, C. J.; Carroll, J. C.; Rosario, E. R.; Barron, A. M. Protective Actions of Sex Steroid Hormones in Alzheimer’s Disease. Frontiers in Neuroendocrinology 2009, 30 (2), 239258,  DOI: 10.1016/j.yfrne.2009.04.015
  455. 455
    Boada, M.; Antunez, C.; López-Arrieta, J.; Caruz, A.; Moreno-Rey, C.; Ramírez-Lorca, R.; Morón, F. J.; Hernández, I.; Mauleón, A.; Rosende-Roca, M.; Martínez-Lage, P.; Marín, J.; Tárraga, L.; Alegret, M.; Pedrajas, J. R.; Urda, N.; Royo, J. L.; Saez, M. E.; Gayán, J.; González-Pérez, A.; Real, L. M.; Ruiz, A.; Galán, J. J. Estrogen Receptor Alpha Gene Variants Are Associated with Alzheimer’s Disease. Neurobiol. Aging 2012, 33 (1), 198.e15198.e24,  DOI: 10.1016/j.neurobiolaging.2010.06.016
  456. 456
    Goodman, Y.; Bruce, A. J.; Cheng, B.; Mattson, M. P. Estrogens Attenuate and Corticosterone Exacerbates Excitotoxicity, Oxidative Injury, and Amyloid β-Peptide Toxicity in Hippocampal Neurons. J. Neurochem. 1996, 66 (5), 18361844,  DOI: 10.1046/j.1471-4159.1996.66051836.x
  457. 457
    Green, P. S.; Gridley, K. E.; Simpkins, J. W. Estradiol Protects against β-Amyloid (25–35)-Induced Toxicity in SK-N-SH Human Neuroblastoma Cells. Neurosci. Lett. 1996, 218 (3), 165168,  DOI: 10.1016/S0304-3940(96)13148-7
  458. 458
    Behl, C.; Widmann, M.; Trapp, T.; Holsboer, F. 17-β Estradiol Protects Neurons from Oxidative Stress-Induced Cell Death in Vitro. Biochem. Biophys. Res. Commun. 1995, 216 (2), 473482,  DOI: 10.1006/bbrc.1995.2647
  459. 459
    Singer, C. A.; Rogers, K. L.; Strickland, T. M.; Dorsa, D. M. Estrogen Protects Primary Cortical Neurons from Glutamate Toxicity. Neurosci. Lett. 1996, 212 (1), 1316,  DOI: 10.1016/0304-3940(96)12760-9
  460. 460
    Zhang, Q.-G.; Raz, L.; Wang, R.; Han, D.; De Sevilla, L.; Yang, F.; Vadlamudi, R. K.; Brann, D. W. Estrogen Attenuates Ischemic Oxidative Damage Via an Estrogen Receptor α-Mediated Inhibition of NADPH Oxidase Activation. J. Neurosci. 2009, 29 (44), 1382313836,  DOI: 10.1523/JNEUROSCI.3574-09.2009
  461. 461
    Spampinato, S. F.; Molinaro, G.; Merlo, S.; Iacovelli, L.; Caraci, F.; Battaglia, G.; Nicoletti, F.; Bruno, V.; Sortino, M. A. Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity. Mol. Pharmacol. 2012, 81 (1), 1220,  DOI: 10.1124/mol.111.074021
  462. 462
    Pike, C. J. Estrogen Modulates Neuronal Bcl-XL Expression and β-Amyloid-Induced Apoptosis: Relevance to Alzheimer’s Disease. J. Neurochem. 1999, 72 (4), 15521563,  DOI: 10.1046/j.1471-4159.1999.721552.x
  463. 463
    Yao, M.; Nguyen, T.-V. V.; Pike, C. J. Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against β-Amyloid Peptide-Induced Neuronal Death. J. Neurosci. 2007, 27 (6), 14221433,  DOI: 10.1523/JNEUROSCI.2382-06.2007
  464. 464
    Zhao, L.; Wu, T.-W.; Brinton, R. D. Estrogen Receptor Subtypes Alpha and Beta Contribute to Neuroprotection and Increased Bcl-2 Expression in Primary Hippocampal Neurons. Brain Res. 2004, 1010 (1–2), 2234,  DOI: 10.1016/j.brainres.2004.02.066
  465. 465
    Suwanna, N.; Thangnipon, W.; Soi-ampornkul, R. Neuroprotective Effects of Diarylpropionitrile against β-Amyloid Peptide-Induced Neurotoxicity in Rat Cultured Cortical Neurons. Neurosci. Lett. 2014, 578, 4449,  DOI: 10.1016/j.neulet.2014.06.029
  466. 466
    Mateos, L.; Persson, T.; Kathozi, S.; Gil-Bea, F. J.; Cedazo-Minguez, A. Estrogen Protects against Amyloid-β Toxicity by Estrogen Receptor α-Mediated Inhibition of Daxx Translocation. Neurosci. Lett. 2012, 506 (2), 245250,  DOI: 10.1016/j.neulet.2011.11.016
  467. 467
    Witty, C. F.; Gardella, L. P.; Perez, M. C.; Daniel, J. M. Short-Term Estradiol Administration in Aging Ovariectomized Rats Provides Lasting Benefits for Memory and the Hippocampus: A Role for Insulin-like Growth Factor-I. Endocrinology 2013, 154 (2), 842852,  DOI: 10.1210/en.2012-1698
  468. 468
    Azcoitia, I.; Sierra, A.; Garcia-Segura, L. M. Neuroprotective Effects of Estradiol in the Adult Rat Hippocampus: Interaction with Insulin-like Growth Factor-I Signalling. J. Neurosci. Res. 1999, 58 (6), 815822,  DOI: 10.1002/(SICI)1097-4547(19991215)58:6<815::AID-JNR8>3.0.CO;2-R
  469. 469
    Rosario, E. R.; Ramsden, M.; Pike, C. J. Progestins Inhibit the Neuroprotective Effects of Estrogen in Rat Hippocampus. Brain Res. 2006, 1099 (1), 206210,  DOI: 10.1016/j.brainres.2006.03.127
  470. 470
    Carroll, J. C.; Rosario, E. R.; Pike, C. J. Progesterone Blocks Estrogen Neuroprotection from Kainate in Middle-Aged Female Rats. Neurosci. Lett. 2008, 445 (3), 229232,  DOI: 10.1016/j.neulet.2008.09.010
  471. 471
    Kim, H.; Bang, O. Y.; Jung, M. W.; Ha, S. D.; Hong, H. S.; Huh, K.; Kim, S. U.; Mook-Jung, I. Neuroprotective Effects of Estrogen against Beta-Amyloid Toxicity Are Mediated by Estrogen Receptors in Cultured Neuronal Cells. Neurosci. Lett. 2001, 302 (1), 5862,  DOI: 10.1016/S0304-3940(01)01659-7
  472. 472
    Benvenuti, S.; Luciani, P.; Vannelli, G. B.; Gelmini, S.; Franceschi, E.; Serio, M.; Peri, A. Estrogen and Selective Estrogen Receptor Modulators Exert Neuroprotective Effects and Stimulate the Expression of Selective Alzheimer’s Disease Indicator-1, a Recently Discovered Antiapoptotic Gene, in Human Neuroblast Long-Term Cell Cultures. J. Clin. Endocrinol. Metab. 2005, 90 (3), 17751782,  DOI: 10.1210/jc.2004-0066
  473. 473
    Mize, A. L.; Young, L. J.; Alper, R. H. Uncoupling of 5-HT1A Receptors in the Brain by Estrogens: Regional Variations in Antagonism by ICI 182,780. Neuropharmacology 2003, 44 (5), 584591,  DOI: 10.1016/S0028-3908(03)00044-3
  474. 474
    Cordey, M.; Pike, C. J. Neuroprotective Properties of Selective Estrogen Receptor Agonists in Cultured Neurons. Brain Res. 2005, 1045 (1–2), 217223,  DOI: 10.1016/j.brainres.2005.03.032
  475. 475
    Fitzpatrick, J. L.; Mize, A. L.; Wade, C. B.; Harris, J. A.; Shapiro, R. A.; Dorsa, D. M. Estrogen-Mediated Neuroprotection against β-Amyloid Toxicity Requires Expression of Estrogen Receptor α or β and Activation of the MAPK Pathway. J. Neurochem. 2002, 82 (3), 674682,  DOI: 10.1046/j.1471-4159.2002.01000.x
  476. 476
    Tiwari-Woodruff, S.; Morales, L. B. J.; Lee, R.; Voskuhl, R. R. Differential Neuroprotective and Antiinflammatory Effects of Estrogen Receptor (ER)α and ERβ Ligand Treatment. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (37), 1481314818,  DOI: 10.1073/pnas.0703783104
  477. 477
    Bourque, M.; Dluzen, D. E.; Di Paolo, T. Signaling Pathways Mediating the Neuroprotective Effects of Sex Steroids and SERMs in Parkinson’s Disease. Front. Neuroendocrinol 2012, 33 (2), 169178,  DOI: 10.1016/j.yfrne.2012.02.003
  478. 478
    Zhao, L.; Brinton, R. D. Estrogen Receptor α and β Differentially Regulate Intracellular Ca2+ Dynamics Leading to ERK Phosphorylation and Estrogen Neuroprotection in Hippocampal Neurons. Brain Res. 2007, 1172, 4859,  DOI: 10.1016/j.brainres.2007.06.092
  479. 479
    Yang, L.-C.; Zhang, Q.-G.; Zhou, C.-F.; Yang, F.; Zhang, Y.-D.; Wang, R.-M.; Brann, D. W. Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus. PLoS One 2010, 5 (5), e9851,  DOI: 10.1371/journal.pone.0009851
  480. 480
    Long, J.; He, P.; Shen, Y.; Li, R. New Evidence of Mitochondria Dysfunction in the Female Alzheimer’s Disease Brain: Deficiency of Estrogen Receptor-β. J. Alzheimer's Dis. 2012, 30 (3), 545558,  DOI: 10.3233/JAD-2012-120283
  481. 481
    Xu, H.; Gouras, G. K.; Greenfield, J. P.; Vincent, B.; Naslund, J.; Mazzarelli, L.; Fried, G.; Jovanovic, J. N.; Seeger, M.; Relkin, N. R.; Liao, F.; Checler, F.; Buxbaum, J. D.; Chait, B. T.; Thinakaran, G.; Sisodia, S. S.; Wang, R.; Greengard, P.; Gandy, S. Estrogen Reduces Neuronal Generation of Alzheimer β-Amyloid Peptides. Nat. Med. 1998, 4 (4), 447451,  DOI: 10.1038/nm0498-447
  482. 482
    Watters, J. J.; Campbell, J. S.; Cunningham, M. J.; Krebs, E. G.; Dorsa, D. M. Rapid MembraneEffects of Steroids in Neuroblastoma Cells: Effects of Estrogen on Mitogen Activated Protein Kinase Signalling Cascade and c-Fos Immediate Early Gene Transcription. Endocrinology 1997, 138 (9), 40304033,  DOI: 10.1210/endo.138.9.5489
  483. 483
    Manthey, D.; Heck, S.; Engert, S.; Behl, C. Estrogen Induces a Rapid Secretion of Amyloid β Precursor Protein via the Mitogen-Activated Protein Kinase Pathway. Eur. J. Biochem. 2001, 268 (15), 42854291,  DOI: 10.1046/j.1432-1327.2001.02346.x
  484. 484
    Li, R.; Shen, Y.; Yang, L.-B.; Lue, L.-F.; Finch, C.; Rogers, J. Estrogen Enhances Uptake of Amyloid β-Protein by Microglia Derived from the Human Cortex. J. Neurochem. 2000, 75 (4), 14471454,  DOI: 10.1046/j.1471-4159.2000.0751447.x
  485. 485
    Harris-White, M. E.; Chu, T.; Miller, S. A.; Simmons, M.; Teter, B.; Nash, D.; Cole, G. M.; Frautschy, S. A. Estrogen (E2) and Glucocorticoid (Gc) Effects on Microglia and Aβ Clearance in Vitro and in Vivo. Neurochem. Int. 2001, 39 (5–6), 435448,  DOI: 10.1016/S0197-0186(01)00051-1
  486. 486
    Bruce-Keller, A. J.; Keeling, J. L.; Keller, J. N.; Huang, F. F.; Camondola, S.; Mattson, M. P. Antiinflammatory Effects of Estrogen on Microglial Activation. Endocrinology 2000, 141 (10), 36463656,  DOI: 10.1210/endo.141.10.7693
  487. 487
    George, S.; Petit, G. H.; Gouras, G. K.; Brundin, P.; Olsson, R. Nonsteroidal Selective Androgen Receptor Modulators and Selective Estrogen Receptor β Agonists Moderate Cognitive Deficits and Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease. ACS Chem. Neurosci. 2013, 4 (12), 15371548,  DOI: 10.1021/cn400133s
  488. 488
    Yue, X.; Lu, M.; Lancaster, T.; Cao, P.; Honda, S. I.; Staufenbiel, M.; Harada, N.; Zhong, Z.; Shen, Y.; Li, R. Brain Estrogen Deficiency Accelerates Aβ Plaque Formation in an Alzheimer’s Disease Animal Model. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (52), 1919819203,  DOI: 10.1073/pnas.0505203102
  489. 489
    Tanzi, R. E.; Moir, R. D.; Wagner, S. L. Clearance of Alzheimer’s Aβ Peptide: The Many Roads to Perdition. Neuron 2004, 43, 605608,  DOI: 10.1016/j.neuron.2004.08.024
  490. 490
    Wei, Y.; Zhou, J.; Wu, J.; Huang, J. ERβ Promotes Aβ Degradation via the Modulation of Autophagy. Cell Death Dis. 2019, 10 (8), 565,  DOI: 10.1038/s41419-019-1786-8
  491. 491
    Hayes, M. T. Parkinson’s Disease and Parkinsonism. American Journal of Medicine 2019, 132 (7), 802807,  DOI: 10.1016/j.amjmed.2019.03.001.
  492. 492
    Popat, R. A.; Van Den Eeden, S. K.; Tanner, C. M.; McGuire, V.; Bernstein, A. L.; Bloch, D. A.; Leimpeter, A.; Nelson, L. M. Effect of Reproductive Factors and Postmenopausal Hormone Use on the Risk of Parkinson Disease. Neurology 2005, 65 (3), 383390,  DOI: 10.1212/01.wnl.0000171344.87802.94
  493. 493
    Wang, P.; Li, J.; Qiu, S.; Wen, H.; Du, J. Hormone Replacement Therapy and Parkinson’s Disease Risk in Women: A Meta-Analysis of 14 Observational Studies. Neuropsychiatr. Dis. Treat. 2015, 11, 5966,  DOI: 10.2147/NDT.S69918
  494. 494
    Currie, L. J.; Harrison, M. B.; Trugman, J. M.; Bennett, J. P.; Wooten, G. F. Postmenopausal Estrogen Use Affects Risk for Parkinson Disease. Arch. Neurol. 2004, 61 (6), 886888,  DOI: 10.1001/archneur.61.6.886
  495. 495
    Bourque, M.; Morissette, M.; Di Paolo, T. Repurposing Sex Steroids and Related Drugs as Potential Treatment for Parkinson’s Disease. Neuropharmacology 2019, 147, 3754
  496. 496
    Blanchet, P. J.; Fang, J.; Hyland, K.; Arnold, L. A.; Mouradian, M. M.; Chase, T. N. Short-Term Effects of High-Dose 17β-Estradiol in Postmenopausal PD Patients: A Crossover Study. Neurology 1999, 53 (1), 9195,  DOI: 10.1212/WNL.53.1.91
  497. 497
    Strijks, E.; Kremer, J. A. M.; Horstink, M. W. I. M. Effects of Female Sex Steroids on Parkinson’s Disease in Postmenopausal Women. Clin. Neuropharmacol. 1999, 22 (2), 9397,  DOI: 10.1097/00002826-199903000-00005
  498. 498
    Dluzen, D. E.; McDermott, J. L.; Anderson, L. I. Tamoxifen Eliminates Estrogen’s Neuroprotective Effect upon MPTP-Induced Neurotoxicity of the Nigrostriatal Dopaminergic System. Neurotoxic. Res. 2001, 3 (3), 291300,  DOI: 10.1007/BF03033268
  499. 499
    Morissette, M.; Sweidi, S. Al; Callier, S.; Di Paolo, T. Estrogen and SERM Neuroprotection in Animal Models of Parkinson’s Disease. Mol. Cell. Endocrinol. 2008, 290 (1–2), 6069,  DOI: 10.1016/j.mce.2008.04.008
  500. 500
    Baraka, A. M.; Korish, A. A.; Soliman, G. A.; Kamal, H. The Possible Role of Estrogen and Selective Estrogen Receptor Modulators in a Rat Model of Parkinson’s Disease. Life Sci. 2011, 88 (19–20), 879885,  DOI: 10.1016/j.lfs.2011.03.010
  501. 501
    McFarland, K.; Price, D. L.; Davis, C. N.; Ma, J.-N.; Bonhaus, D. W.; Burstein, E. S.; Olsson, R. AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson’s Disease Rat Model. ACS Chem. Neurosci. 2013, 4 (9), 12491255,  DOI: 10.1021/cn400132u
  502. 502
    Sierra, A.; Gottfried-Blackmore, A.; Milner, T. A.; McEwen, B. S.; Bulloch, K. Steroid Hormone Receptor Expression and Function in Microglia. Glia 2008, 56 (6), 659674,  DOI: 10.1002/glia.20644
  503. 503
    Barreto, G.; Santos-Galindo, M.; Diz-Chaves, Y.; Pernía, O.; Carrero, P.; Azcoitia, I.; Garcia-Segura, L. M. Selective Estrogen Receptor Modulators Decrease Reactive Astrogliosis in the Injured Brain: Effects of Aging and Prolonged Depletion of Ovarian Hormones. Endocrinology 2009, 150 (11), 50105015,  DOI: 10.1210/en.2009-0352
  504. 504
    Maglione, A.; Rolla, S.; De Mercanti, S. F.; Cutrupi, S.; Clerico, M. The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View. Cells 2019, 8 (10), 1280,  DOI: 10.3390/cells8101280
  505. 505
    Villa, A.; Vegeto, E.; Poletti, A.; Maggi, A. Estrogens, Neuroinflammation, and Neurodegeneration. Endocrine Reviews 2016, 37 (4), 372402,  DOI: 10.1210/er.2016-1007
  506. 506
    Lewis, D. K.; Johnson, A. B.; Stohlgren, S.; Harms, A.; Sohrabji, F. Effects of Estrogen Receptor Agonists on Regulation of the Inflammatory Response in Astrocytes from Young Adult and Middle-Aged Female Rats. J. Neuroimmunol. 2008, 195 (1–2), 4759,  DOI: 10.1016/j.jneuroim.2008.01.006
  507. 507
    Vegeto, E.; Belcredito, S.; Etteri, S.; Ghisletti, S.; Brusadelli, A.; Meda, C.; Krust, A.; Dupont, S.; Ciana, P.; Chambon, P.; Maggi, A. Estrogen Receptor-α Mediates the Brain Antiinflammatory Activity of Estradiol. Proc. Natl. Acad. Sci. U. S. A. 2003, 100 (16), 96149619,  DOI: 10.1073/pnas.1531957100
  508. 508
    Bebo, B. F.; Fyfe-Johnson, A.; Adlard, K.; Beam, A. G.; Vandenbark, A. A.; Offner, H. Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains. J. Immunol. 2001, 166 (3), 20802089,  DOI: 10.4049/jimmunol.166.3.2080
  509. 509
    Ito, A.; Bebo, B. F.; Matejuk, A.; Zamora, A.; Silverman, M.; Fyfe-Johnson, A.; Offner, H. Estrogen Treatment Down-Regulates TNF-α Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice. J. Immunol. 2001, 167 (1), 542552,  DOI: 10.4049/jimmunol.167.1.542
  510. 510
    Liu, H. Y.; Buenafe, A. C.; Matejuk, A.; Ito, A.; Zamora, A.; Dwyer, J.; Vandenbark, A. A.; Offner, H. Estrogen Inhibition of EAE Involves Effects on Dendritic Cell Function. J. Neurosci. Res. 2002, 70 (2), 238248,  DOI: 10.1002/jnr.10409
  511. 511
    Spence, R. D.; Hamby, M. E.; Umeda, E.; Itoh, N.; Du, S.; Wisdom, A. J.; Cao, Y.; Bondar, G.; Lam, J.; Ao, Y.; Sandoval, F.; Suriany, S.; Sofroniew, M. V.; Voskuhl, R. R. Neuroprotection Mediated through Estrogen Receptor-α in Astrocytes. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (21), 88678872,  DOI: 10.1073/pnas.1103833108
  512. 512
    Kim, S.; Liva, S. M.; Dalal, M. A.; Verity, M. A.; Voskuhl, R. R. Estriol Ameliorates Autoimmune Demyelinating Disease: Implications for Multiple Sclerosis. Neurology 1999, 52 (6), 12301238,  DOI: 10.1212/WNL.52.6.1230
  513. 513
    Spence, R. D.; Wisdom, A. J.; Cao, Y.; Hill, H. M.; Mongerson, C. R. L.; Stapornkul, B.; Itoh, N.; Sofroniew, M. V.; Voskuhl, R. R. Estrogen Mediates Neuroprotection and Anti-Inflammatory Effects during EAE through ERα Signaling on Astrocytes but Not through ERβ Signaling on Astrocytes or Neurons. J. Neurosci. 2013, 33 (26), 1092410933,  DOI: 10.1523/JNEUROSCI.0886-13.2013
  514. 514
    Sicotte, N. L.; Liva, S. M.; Klutch, R.; Pfeiffer, P.; Bouvier, S.; Odesa, S.; Wu, T. C. J.; Voskuhl, R. R. Treatment of Multiple Sclerosis with the Pregnancy Hormone Estriol. Ann. Neurol. 2002, 52 (4), 421428,  DOI: 10.1002/ana.10301
  515. 515
    Vukusic, S.; Ionescu, I.; El-Etr, M.; Schumacher, M.; Baulieu, E. E.; Cornu, C.; Confavreux, C. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART′MUS) Trial: Rationale, Objectives and State of Advancement. J. Neurol. Sci. 2009, 286 (1–2), 114118,  DOI: 10.1016/j.jns.2009.08.056
  516. 516
    Pozzilli, C.; De Giglio, L.; Barletta, V. T.; Marinelli, F.; De Angelis, F.; Gallo, V.; Pagano, V. A.; Marini, S.; Piattella, M. C.; Tomassini, V.; Pantano, P. Oral Contraceptives Combined with Interferon b in Multiple Sclerosis. Neurol. Neuroimmunol. NeuroInflammation 2015, 2 (4), e120,  DOI: 10.1212/NXI.0000000000000120
  517. 517
    Voskuhl, R. R.; Wang, H. J.; Wu, T. C. J.; Sicotte, N. L.; Nakamura, K.; Kurth, F.; Itoh, N.; Bardens, J.; Bernard, J. T.; Corboy, J. R.; Cross, A. H.; Dhib-Jalbut, S.; Ford, C. C.; Frohman, E. M.; Giesser, B.; Jacobs, D.; Kasper, L. H.; Lynch, S.; Parry, G.; Racke, M. K.; Reder, A. T.; Rose, J.; Wingerchuk, D. M.; MacKenzie-Graham, A. J.; Arnold, D. L.; Tseng, C. H.; Elashoff, R. Estriol Combined with Glatiramer Acetate for Women with Relapsing-Remitting Multiple Sclerosis: A Randomised, Placebo-Controlled, Phase 2 Trial. Lancet Neurol. 2016, 15 (1), 3546,  DOI: 10.1016/S1474-4422(15)00322-1
  518. 518
    Rossouw, J. E.; Anderson, G. L.; Prentice, R. L.; LaCroix, A. Z.; Kooperberg, C.; Stefanick, M. L.; Jackson, R. D.; Beresford, S. A. A.; Howard, B. V.; Johnson, K. C.; Kotchen, J. M.; Ockene, J. Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women’s Health Initiative Randomized Controlled Trial. JAMA, J. Am. Med. Assoc. 2002, 288 (3), 321333,  DOI: 10.1001/jama.288.3.321
  519. 519
    Paterni, I.; Granchi, C.; Katzenellenbogen, J. A.; Minutolo, F. Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential. Steroids 2014, 90, 1329,  DOI: 10.1016/j.steroids.2014.06.012
  520. 520
    Brzozowski, A. M.; Pike, A. C. W.; Dauter, Z.; Hubbard, R. E.; Bonn, T.; Engström, O.; Öhman, L.; Greene, G. L.; Gustafsson, J.-Å.; Carlquist, M. Molecular Basis of Agonism and Antagonism in the Oestrogen Receptor. Nature 1997, 389 (6652), 753758,  DOI: 10.1038/39645
  521. 521
    Pike, A. C. W.; Brzozowski, A. M.; Hubbard, R. E.; Bonn, T.; Thorsell, A.-G.; Engström, O.; Ljunggren, J.; Gustafsson, J.-Å.; Carlquist, M. Structure of the Ligand-Binding Domain of Oestrogen Receptor Beta in the Presence of a Partial Agonist and a Full Antagonist. EMBO J. 1999, 18 (17), 46084618,  DOI: 10.1093/emboj/18.17.4608
  522. 522
    Shiau, A. K.; Barstad, D.; Radek, J. T.; Meyers, M. J.; Nettles, K. W.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Agard, D. A.; Greene, G. L. Structural Characterization of a Subtype-Selective Ligand Reveals a Novel Mode of Estrogen Receptor Antagonism. Nat. Struct. Biol. 2002, 9 (5), 359364,  DOI: 10.1038/nsb787
  523. 523
    Levenson, A. S.; Craig Jordan, V. The Key to the Antiestrogenic Mechanism of Raloxifene Is Amino Acid 351 (Aspartate) in the Estrogen Receptor. Cancer Res. 1998, 58 (9), 18721875
  524. 524
    Heldring, N.; Pike, A.; Andersson, S.; Matthews, J.; Cheng, G.; Hartman, J.; Tujague, M.; Ström, A.; Treuter, E.; Warner, M.; Gustafsson, J.-Å. Estrogen Receptors: How Do They Signal and What Are Their Targets. Physiol. Rev. 2007, 87 (3), 905931,  DOI: 10.1152/physrev.00026.2006
  525. 525
    Nilsson, S.; Koehler, K. F.; Gustafsson, J.-Å. Development of Subtype-Selective Oestrogen Receptor-Based Therapeutics. Nat. Rev. Drug Discovery 2011, 10 (10), 778792,  DOI: 10.1038/nrd3551
  526. 526
    Jordan, V. C. Antiestrogens and Selective Estrogen Receptor Modulators as Multifunctional Medicines. 1. Receptor Interactions. J. Med. Chem. 2003, 46, 883908,  DOI: 10.1021/jm020449y
  527. 527
    Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Pyrazole Ligands: Structure - Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists. J. Med. Chem. 2000, 43 (26), 49344947,  DOI: 10.1021/jm000170m
  528. 528
    Meyers, M. J.; Sun, J.; Carlson, K. E.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen Receptor Subtype-Selective Ligands: Asymmetric Synthesis and Biological Evaluation of Cis- and Trans-5,11-Dialkyl-5,6,11,12- Tetrahydrochrysenes. J. Med. Chem. 1999, 42 (13), 24562468,  DOI: 10.1021/jm990101b
  529. 529
    Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen Receptor-β Potency-Selective Ligands: Structure-Activity Relationship Studies of Diarylpropionitriles and Their Acetylene and Polar Analogues. J. Med. Chem. 2001, 44 (24), 42304251,  DOI: 10.1021/jm010254a
  530. 530
    Minutolo, F.; Bertini, S.; Granchi, C.; Marchitiello, T.; Prota, G.; Rapposelli, S.; Tuccinardi, T.; Martinelli, A.; Gunther, J. R.; Carlson, K. E.; Katzenellenbogen, J. A.; Macchia, M. Structural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor β. J. Med. Chem. 2009, 52 (3), 858867,  DOI: 10.1021/jm801458t
  531. 531
    Malamas, M. S.; Manas, E. S.; McDevitt, R. E.; Gunawan, I.; Xu, Z. B.; Collini, M. D.; Miller, C. P.; Dinh, T.; Henderson, R. A.; Keith, J. C.; Harris, H. A. Design and Synthesis of Aryl Diphenolic Azoles as Potent and Selective Estrogen Receptor-β Ligands. J. Med. Chem. 2004, 47 (21), 50215040,  DOI: 10.1021/jm049719y
  532. 532
    Komm, B. S.; Mirkin, S. An Overview of Current and Emerging SERMs. J. Steroid Biochem. Mol. Biol. 2014, 143, 207222,  DOI: 10.1016/j.jsbmb.2014.03.003
  533. 533
    Patel, H. K.; Bihani, T. Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs) in Cancer Treatment. Pharmacol. Ther. 2018, 186, 124,  DOI: 10.1016/j.pharmthera.2017.12.012
  534. 534
    Henke, B. R.; Drewry, D. H.; Jones, S. A.; Stewart, E. L.; Weaver, S. L.; Wiethe, R. W. 2-Amino-4,6-Diarylpyridines as Novel Ligands for the Estrogen Receptor. Bioorg. Med. Chem. Lett. 2001, 11 (14), 19391942,  DOI: 10.1016/S0960-894X(01)00321-3
  535. 535
    Renaud, J.; Bischoff, S. F.; Buhl, T.; Floersheim, P.; Fournier, B.; Geiser, M.; Halleux, C.; Kallen, J.; Keller, H.; Ramage, P. Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure-Activity Relationship of ERα-Selective Tetrahydroisoquinoline Ligands. J. Med. Chem. 2005, 48 (2), 364379,  DOI: 10.1021/jm040858p
  536. 536
    Hill, R. A.; Kouremenos, K.; Tull, D.; Maggi, A.; Schroeder, A.; Gibbons, A.; Kulkarni, J.; Sundram, S.; Du, X. Bazedoxifene – a Promising Brain Active SERM That Crosses the Blood Brain Barrier and Enhances Spatial Memory. Psychoneuroendocrinology 2020, 121, 104830,  DOI: 10.1016/j.psyneuen.2020.104830
  537. 537
    Wakeling, A. E.; Dukes, M.; Bowler, J. A Potent Specific Pure Antiestrogen with Clinical Potential. Cancer Res. 1991, 51 (15), 38673873
  538. 538
    Garner, F.; Shomali, M.; Paquin, D.; Lyttle, C. R.; Hattersley, G. RAD1901: A Novel, Orally Bioavailable Selective Estrogen Receptor Degrader That Demonstrates Antitumor Activity in Breast Cancer Xenograft Models. Anti-Cancer Drugs 2015, 26 (9), 948956,  DOI: 10.1097/CAD.0000000000000271
  539. 539
    Conlan, M. G.; de Vries, E. F. J.; Glaudemans, A.; Wang, Y.; Troy, S. Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women. Eur. J. Drug Metab. Pharmacokinet. 2020, 45 (5), 675689,  DOI: 10.1007/s13318-020-00635-3

Cited By


This article has not yet been cited by other publications.

  • Abstract

    Figure 1

    Figure 1. Nuclear receptors. (a) Overview over the nuclear receptor superfamily comprising 48 members in human.(30) (b) Basic mechanism of genomic nuclear receptor function. NRs of the NR1 family like LXRs and PPARs bind to their specific NRE within the promoter region of their target genes as obligate heterodimers with RXR. In the absence of ligand binding, these heterodimers associate with corepressor complexes, which results in repression of transcription. Conformational changes of the complex occur upon ligand binding, which involves displacement of the corepressor complex and subsequent coactivator recruitment, resulting in the transcription of target genes. (c) Exemplified indirect genomic action of nuclear receptors. For example, NFκB-regulated pro-inflammatory genes are differently controlled by NRs. Monomers such as PPARγ or LXR can undergo SUMOylation upon ligand binding and recruit corepressors to inhibit gene expression via NFκB (p50 and p65 subunits) interaction with its response elements.

    Scheme 1

    Scheme 1. Selected PPAR Ligands Used in Studies on Neurodegeneration or with Preferable Tool Compound Characteristics

    Scheme 2

    Scheme 2. RevERB Modulators

    Scheme 3

    Scheme 3. Selected LXR Ligands

    Scheme 4

    Scheme 4. Potent and Selective VDR Ligands (Agonists 3740; Antagonist 41) from the Literature(214−217) as Potential Tools for Functional Studies in Neurodegeneration

    Figure 2

    Figure 2. Role of RXR in NR heterodimers. Permissive heterodimers respond to RXR ligands and to ligands of the heterodimer partner. The presence of ligands for both partners causes synergistic activation. Nonpermissive heterodimers can only be activated by ligands of the heterodimer partner.(21)

    Scheme 5

    Scheme 5. Selected RXR Ligands

    Scheme 6

    Scheme 6. TLX Ligands Reported in the Literature(291,292,315)

    Figure 3

    Figure 3. Comparison of the crystal structures of “classical” nuclear receptors (RXRα) and NR4A receptors (Nur77). (a) The apo structure of the RXRα LBD (pdb 3R29) in complex with the corepressor peptide SMRT (magenta) reveals the NR in its inactive state in which the C-terminal α-helix (H12, colored red) comprises the AF-2 in an unordered conformation. (b) The ligand-activated state of RXRα (pdb 3OAP) shows the NR cocrystallized with its endogenous ligand 9-cis RA (43) and the coactivator peptide TIF2 (neon green) with H12 in its active conformation. (c) The apo structure of the Nur77 LBD (pdb 3V3E) reveals the NR in an autoactivated state with H12 coordinated to the LBD core without a bound ligand. (d) Ligand-activated cocrystal structure (pdb 6KZ5) of the Nur77 LBD in complex with agonist Csn-B (68, purple) superimposed with ligand binding pockets and their respective ligands from other Nur77 cocrystal structures revealing other binding sites with high solvent exposure. Csn-B (68, purple) is bound at the dimeric interface, THPN (71, teal, pdb 4JGV) is protruding toward a sub-pocket between H5 and H7, and TMPA (69, blue and orange, pdb 3V3Q) is bound to two different sites. Site A (orange) is located at the interaction site of H12, which resembles the binding pockets identified for covalently bound Nurr1 ligands DHI (83) and PGA1 (80), while site B (blue) constitutes a cavity on the surface close to helices 1, 5, and 8. Alignment and superposition of the structures were performed in MOE 2020.09.

    Scheme 7

    Scheme 7. Nur77 Ligands Reported in the Literature(325,330,350,354,356,357)

    Figure 4

    Figure 4. NR4A receptor mechanisms of action. (a) The constitutively active NR4A receptors (Nur77, Nurr1, and NOR-1) can directly bind to specific response elements as a homodimer, as a heterodimer with RXR (only Nur77 and Nurr1), or as a monomer. Sumoylation of the respective NR causes monomerization, and these monomers activate NBRE. NR4A homodimers bind to NurRE, while NR4A:RXR heterodimers bind to DR5 response elements. (b) Additionally, Nurr1 monomers directly interact with p65 on the NFκB RE upon sumoylation and recruit the CoREST corepressor complex, which results in suppression of NFκB-regulated pro-inflammatory genes. Abbreviations: CoREST, REST corepressor; DR5, direct repeat spaced by five nucleotides; NBRE, NGFI-B responsive element; NFκB, nuclear factor-κB; NOR-1, neuron derived orphan receptor 1; NurRE, Nur response element; Nurr1, nuclear receptor related-1 protein; RXR, retinoid X receptor.

    Scheme 8

    Scheme 8. Nurr1 Modulators Reported in the Literature(360,396−398,418,422)

    Scheme 9

    Scheme 9. Nurr1-RXR Heterodimer-Specific RXR Agonists Reported in the Literature(402,403,435,436,438,439)

    Scheme 10

    Scheme 10. NOR-1 Activating Compounds

    Scheme 11

    Scheme 11. ER Ligands
  • References

    ARTICLE SECTIONS
    Jump To

    This article references 539 other publications.

    1. 1
      Prince, M.; Bryce, R.; Albanese, E.; Wimo, A.; Ribeiro, W.; Ferri, C. P. The Global Prevalence of Dementia: A Systematic Review and Metaanalysis. Alzheimer's Dementia 2013, 9 (1), 6375.e2,  DOI: 10.1016/j.jalz.2012.11.007
    2. 2
      Moutinho, M.; Codocedo, J. F.; Puntambekar, S. S.; Landreth, G. E. Nuclear Receptors as Therapeutic Targets for Neurodegenerative Diseases: Lost in Translation. Annu. Rev. Pharmacol. Toxicol. 2019, 59, 237261
    3. 3
      Abraha, I.; Rimland, J. M.; Trotta, F. M.; Dell’Aquila, G.; Cruz-Jentoft, A.; Petrovic, M.; Gudmundsson, A.; Soiza, R.; O’Mahony, D.; Guaita, A.; Cherubini, A. Systematic Review of Systematic Reviews of Non-Pharmacological Interventions to Treat Behavioural Disturbances in Older Patients with Dementia. The SENATOR-OnTop Series. BMJ. Open 2017, 7, e012759,  DOI: 10.1136/bmjopen-2016-012759
    4. 4
      Schmidt, R.; Hofer, E.; Bouwman, F. H.; Buerger, K.; Cordonnier, C.; Fladby, T.; Galimberti, D.; Georges, J.; Heneka, M. T.; Hort, J.; Laczó, J.; Molinuevo, J. L.; O’Brien, J. T.; Religa, D.; Scheltens, P.; Schott, J. M.; Sorbi, S. EFNS-ENS/EAN Guideline on Concomitant Use of Cholinesterase Inhibitors and Memantine in Moderate to Severe Alzheimer’s Disease. Eur. J. Neurol. 2015, 22 (6), 889898,  DOI: 10.1111/ene.12707
    5. 5
      McShane, R.; Areosa Sastre, A.; Minakaran, N. Memantine for Dementia. Cochrane Database Syst. Rev. 2006, No. 2. DOI: 10.1002/14651858.CD003154.pub5
    6. 6
      Birks, J.; Grimley Evans, J. Ginkgo Biloba for Cognitive Impairment and Dementia. Cochrane Database Syst. Rev. 2009, No. 1. DOI: 10.1002/14651858.CD003120.pub3
    7. 7
      Masters, C. L.; Bateman, R.; Blennow, K.; Rowe, C. C.; Sperling, R. A.; Cummings, J. L. Alzheimer’s Disease. Nat. Rev. Dis. Prim. 2015, 1 (1), 15056,  DOI: 10.1038/nrdp.2015.56
    8. 8
      Congdon, E. E.; Sigurdsson, E. M. Tau-Targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 2018, 14 (7), 399415,  DOI: 10.1038/s41582-018-0013-z
    9. 9
      Panza, F.; Lozupone, M.; Logroscino, G.; Imbimbo, B. P. A Critical Appraisal of Amyloid-β-Targeting Therapies for Alzheimer Disease. Nat. Rev. Neurol. 2019, 15 (2), 7388,  DOI: 10.1038/s41582-018-0116-6
    10. 10
      Uliassi, E.; Gandini, A.; Perone, R. C.; Bolognesi, M. L. Neuroregeneration versus Neurodegeneration: Toward a Paradigm Shift in Alzheimer’s Disease Drug Discovery. Future Med. Chem. 2017, 9 (10), 9951013,  DOI: 10.4155/fmc-2017-0038
    11. 11
      Wang, J.; Gu, B. J.; Masters, C. L.; Wang, Y.-J. A Systemic View of Alzheimer Disease — Insights from Amyloid-β Metabolism beyond the Brain. Nat. Rev. Neurol. 2017, 13 (10), 612623,  DOI: 10.1038/nrneurol.2017.111
    12. 12
      Elkouzi, A.; Vedam-Mai, V.; Eisinger, R. S.; Okun, M. S. Emerging Therapies in Parkinson Disease — Repurposed Drugs and New Approaches. Nat. Rev. Neurol. 2019, 15 (4), 204223,  DOI: 10.1038/s41582-019-0155-7
    13. 13
      de Lau, L. M. L.; Breteler, M. M. B. Epidemiology of Parkinson’s Disease. Lancet Neurol. 2006, 5 (6), 525535,  DOI: 10.1016/S1474-4422(06)70471-9
    14. 14
      Parkinson’s Disease in Adults. NICE Guidelines, 2017, NG71.
    15. 15
      Deuschl, G.; de Bie, R. M. A. New Therapeutic Developments for Parkinson Disease. Nat. Rev. Neurol. 2019, 15 (2), 6869,  DOI: 10.1038/s41582-019-0133-0
    16. 16
      Doshi, A.; Chataway, J. Multiple Sclerosis, a Treatable Disease. Clin. Med. (Northfield. Il). 2016, 16 (6), s53s59,  DOI: 10.7861/clinmedicine.16-6-s53
    17. 17
      Tintore, M.; Vidal-Jordana, A.; Sastre-Garriga, J. Treatment of Multiple Sclerosis — Success from Bench to Bedside. Nat. Rev. Neurol. 2019, 15 (1), 5358,  DOI: 10.1038/s41582-018-0082-z
    18. 18
      Stangel, M.; Kuhlmann, T.; Matthews, P. M.; Kilpatrick, T. J. Achievements and Obstacles of Remyelinating Therapies in Multiple Sclerosis. Nat. Rev. Neurol. 2017, 13 (12), 742754,  DOI: 10.1038/nrneurol.2017.139
    19. 19
      Zhao, C.; Deng, W.; Gage, F. H. Mechanisms and Functional Implications of Adult Neurogenesis. Cell 2008, 132 (4), 645660,  DOI: 10.1016/j.cell.2008.01.033
    20. 20
      Germain, P.; Staels, B.; Dacquet, C.; Spedding, M.; Laudet, V. Overview of Nomenclature of Nuclear Receptors. Pharmacol. Rev. 2006, 58 (4), 685704,  DOI: 10.1124/pr.58.4.2
    21. 21
      Aranda, A.; Pascual, A. Nuclear Hormone Receptors and Gene Expression. Physiol. Rev. 2001, 81 (3), 12691304,  DOI: 10.1152/physrev.2001.81.3.1269
    22. 22
      De Bosscher, K.; Desmet, S. J.; Clarisse, D.; Estébanez-Perpiña, E.; Brunsveld, L. Nuclear Receptor Crosstalk — Defining the Mechanisms for Therapeutic Innovation. Nat. Rev. Endocrinol. 2020, 16 (7), 363377,  DOI: 10.1038/s41574-020-0349-5
    23. 23
      Evans, R. M.; Mangelsdorf, D. J. Nuclear Receptors, RXR, and the Big Bang. Cell 2014, 157, 255266,  DOI: 10.1016/j.cell.2014.03.012
    24. 24
      Rastinejad, F.; Huang, P.; Chandra, V.; Khorasanizadeh, S. Understanding Nuclear Receptor Form and Function Using Structural Biology. J. Mol. Endocrinol. 2013, 51 (3), T1T21,  DOI: 10.1530/JME-13-0173
    25. 25
      Negishi, M.; Kobayashi, K.; Sakuma, T.; Sueyoshi, T. Nuclear Receptor Phosphorylation in Xenobiotic Signal Transduction. J. Biol. Chem. 2020, 295 (45), 1521015225,  DOI: 10.1074/jbc.REV120.007933
    26. 26
      Rastinejad, F.; Ollendorff, V.; Polikarpov, I. Nuclear Receptor Full-Length Architectures: Confronting Myth and Illusion with High Resolution. Trends Biochem. Sci. 2015, 40 (1), 1624,  DOI: 10.1016/j.tibs.2014.10.011
    27. 27
      Weikum, E. R.; Liu, X.; Ortlund, E. A. The Nuclear Receptor Superfamily: A Structural Perspective. Protein Sci. 2018, 27, 18761892,  DOI: 10.1002/pro.3496
    28. 28
      Bain, D. L.; Heneghan, A. F.; Connaghan-Jones, K. D.; Miura, M. T. Nuclear Receptor Structure: Implications for Function. Annu. Rev. Physiol. 2007, 69 (1), 201220,  DOI: 10.1146/annurev.physiol.69.031905.160308
    29. 29
      Benoit, G.; Cooney, A.; Giguere, V.; Ingraham, H.; Lazar, M.; Muscat, G.; Perlmann, T.; Renaud, J.-P.; Schwabe, J.; Sladek, F.; Tsai, M.-J.; Laudet, V. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors. Pharmacol. Rev. 2006, 58 (4), 798836,  DOI: 10.1124/pr.58.4.10
    30. 30
      Robinson-Rechavi, M.; Garcia, H. E.; Laudet, V. The Nuclear Receptor Superfamily. J. Cell Sci. 2003, 116 (4), 585586,  DOI: 10.1242/jcs.00247
    31. 31
      Michalik, L.; Auwerx, J.; Berger, J. P.; Chatterjee, V. K.; Glass, C. K.; Gonzalez, F. J.; Grimaldi, P. A.; Kadowaki, T.; Lazar, M. A.; O’Rahilly, S.; Palmer, C. N. A.; Plutzky, J.; Reddy, J. K.; Spiegelman, B. M.; Staels, B.; Wahli, W. International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors. Pharmacol. Rev. 2006, 58 (4), 726741,  DOI: 10.1124/pr.58.4.5
    32. 32
      Warden, A.; Truitt, J.; Merriman, M.; Ponomareva, O.; Jameson, K.; Ferguson, L. B.; Mayfield, R. D.; Harris, R. A. Localization of PPAR Isotypes in the Adult Mouse and Human Brain. Sci. Rep. 2016, 6, 27681,  DOI: 10.1038/srep27618
    33. 33
      Gellrich, L.; Heitel, P.; Heering, J.; Kilu, W.; Pollinger, J.; Goebel, T.; Kahnt, A.; Arifi, S.; Pogoda, W.; Paulke, A.; Steinhilber, D.; Proschak, E.; Wurglics, M.; Schubert-Zsilavecz, M.; Chaikuad, A.; Knapp, S.; Bischoff, I.; Fürst, R.; Merk, D. L-Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ. J. Med. Chem. 2020, 63 (13), 67276740,  DOI: 10.1021/acs.jmedchem.9b02150
    34. 34
      Proschak, E.; Heitel, P.; Kalinowsky, L.; Merk, D. Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery. J. Med. Chem. 2017, 60 (13), 52355266,  DOI: 10.1021/acs.jmedchem.6b01287
    35. 35
      Wahli, W.; Michalik, L. PPARs at the Crossroads of Lipid Signaling and Inflammation. Trends Endocrinol. Metab. 2012, 23, 351363,  DOI: 10.1016/j.tem.2012.05.001
    36. 36
      Lamers, C.; Schubert-Zsilavecz, M.; Merk, D. Therapeutic Modulators of Peroxisome Proliferator-Activated Receptors (PPAR): A Patent Review (2008–Present). Expert Opin. Ther. Pat. 2012, 22 (7), 803841,  DOI: 10.1517/13543776.2012.699042
    37. 37
      Lu, C.-H.; Yang, C.-Y.; Li, C.-Y.; Hsieh, C.; Ou, H.-T. Lower Risk of Dementia with Pioglitazone, Compared with Other Second-Line Treatments, in Metformin-Based Dual Therapy: A Population-Based Longitudinal Study. Diabetologia 2018, 61 (3), 562573,  DOI: 10.1007/s00125-017-4499-5
    38. 38
      Heneka, M. T.; Fink, A.; Doblhammer, G. Effect of Pioglitazone Medication on the Incidence of Dementia. Ann. Neurol. 2015, 78 (2), 284294,  DOI: 10.1002/ana.24439
    39. 39
      Chou, P.-S.; Ho, B.-L.; Yang, Y.-H. Effects of Pioglitazone on the Incidence of Dementia in Patients with Diabetes. J. Diabetes Complications 2017, 31 (6), 10531057,  DOI: 10.1016/j.jdiacomp.2017.01.006
    40. 40
      Kummer, M. P.; Heneka, M. T. PPARs in Alzheimer’s Disease. PPAR Res. 2008, 2008, 403896,  DOI: 10.1155/2008/403896
    41. 41
      Heneka, M. T.; Reyes-Irisarri, E.; Hull, M.; Kummer, M. P. Impact and Therapeutic Potential of PPARs in Alzheimers Disease. Curr. Neuropharmacol. 2011, 9 (4), 643650,  DOI: 10.2174/157015911798376325
    42. 42
      Du, J.; Zhang, L.; Liu, S.; Zhang, C.; Huang, X.; Li, J.; Zhao, N.; Wang, Z. PPARγ Transcriptionally Regulates the Expression of Insulin-Degrading Enzyme in Primary Neurons. Biochem. Biophys. Res. Commun. 2009, 383 (4), 485490,  DOI: 10.1016/j.bbrc.2009.04.047
    43. 43
      Quan, Q.; Qian, Y.; Li, X.; Li, M. Pioglitazone Reduces β Amyloid Levels via Inhibition of PPARγ Phosphorylation in a Neuronal Model of Alzheimer’s Disease. Front. Aging Neurosci. 2019, 11, 178,  DOI: 10.3389/fnagi.2019.00178
    44. 44
      Sastre, M.; Dewachter, I.; Rossner, S.; Bogdanovic, N.; Rosen, E.; Borghgraef, P.; Evert, B. O.; Dumitrescu-Ozimek, L.; Thal, D. R.; Landreth, G.; Walter, J.; Klockgether, T.; Van Leuven, F.; Heneka, M. T. Nonsteroidal Anti-Inflammatory Drugs Repress β-Secretase Gene Promoter Activity by the Activation of PPARγ. Proc. Natl. Acad. Sci. U. S. A. 2006, 103 (2), 443448,  DOI: 10.1073/pnas.0503839103
    45. 45
      Sastre, M.; Dewachter, I.; Landreth, G. E.; Willson, T. M.; Klockgether, T.; Van Leuven, F.; Heneka, M. T. Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-γ Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of β-Secretase. J. Neurosci. 2003, 23 (30), 97969804,  DOI: 10.1523/JNEUROSCI.23-30-09796.2003
    46. 46
      Yang, S.; Chen, Z.; Cao, M.; Li, R.; Wang, Z.; Zhang, M. Pioglitazone Ameliorates Aβ42 Deposition in Rats with Diet-Induced Insulin Resistance Associated with AKT/GSK3β Activation. Mol. Med. Rep. 2017, 15 (5), 25882594,  DOI: 10.3892/mmr.2017.6342
    47. 47
      Chang, K. L.; Wong, L. R.; Pee, H. N.; Yang, S.; Ho, P. C. L. Reverting Metabolic Dysfunction in Cortex and Cerebellum of APP/PS1Mice, a Model for Alzheimer’s Disease by Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Agonist. Mol. Neurobiol. 2019, 56 (11), 72677283,  DOI: 10.1007/s12035-019-1586-2
    48. 48
      Yu, Y.; Li, X.; Blanchard, J.; Li, Y.; Iqbal, K.; Liu, F.; Gong, C.-X. Insulin Sensitizers Improve Learning and Attenuate Tau Hyperphosphorylation and Neuroinflammation in 3xTg-AD Mice. J. Neural Transm. 2015, 122 (4), 593606,  DOI: 10.1007/s00702-014-1294-z
    49. 49
      Du, J.; Sun, B.; Chen, K.; Fan, L.; Wang, Z. Antagonist of Peroxisome Proliferator-Activated Receptor γ Induces Cerebellar Amyloid-β Levels and Motor Dysfunction in APP/PS1 Transgenic Mice. Biochem. Biophys. Res. Commun. 2009, 384 (3), 357361,  DOI: 10.1016/j.bbrc.2009.04.148
    50. 50
      Fernandez-Martos, C. M.; Atkinson, R. A. K.; Chuah, M. I.; King, A. E.; Vickers, J. C. Combination Treatment with Leptin and Pioglitazone in a Mouse Model of Alzheimer’s Disease. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2017, 3 (1), 92106,  DOI: 10.1016/j.trci.2016.11.002
    51. 51
      Chen, J.; Li, S.; Sun, W.; Li, J. Anti-Diabetes Drug Pioglitazone Ameliorates Synaptic Defects in AD Transgenic Mice by Inhibiting Cyclin-Dependent Kinase5 Activity. PLoS One 2015, 10, e0123864  DOI: 10.1371/journal.pone.0123864
    52. 52
      Mandrekar-Colucci, S.; Karlo, J. C.; Landreth, G. E. Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer’s Disease. J. Neurosci. 2012, 32 (30), 1011710128,  DOI: 10.1523/JNEUROSCI.5268-11.2012
    53. 53
      Papadopoulos, P.; Rosa-Neto, P.; Rochford, J.; Hamel, E. Pioglitazone Improves Reversal Learning and Exerts Mixed Cerebrovascular Effects in a Mouse Model of Alzheimer’s Disease with Combined Amyloid-β and Cerebrovascular Pathology. PLoS One 2013, 8 (7), e68612,  DOI: 10.1371/journal.pone.0068612
    54. 54
      Prakash, A.; Kumar, A. Role of Nuclear Receptor on Regulation of BDNF and Neuroinflammation in Hippocampus of β-Amyloid Animal Model of Alzheimer’s Disease. Neurotoxic. Res. 2014, 25 (5), 335347,  DOI: 10.1007/s12640-013-9437-9
    55. 55
      Hamano, T.; Shirafuji, N.; Makino, C.; Yen, S.-H.; Kanaan, N. M.; Ueno, A.; Suzuki, J.; Ikawa, M.; Matsunaga, A.; Yamamura, O.; Kuriyama, M.; Nakamoto, Y. Pioglitazone Prevents Tau Oligomerization. Biochem. Biophys. Res. Commun. 2016, 478 (3), 10351042,  DOI: 10.1016/j.bbrc.2016.08.016
    56. 56
      Cho, D.-H.; Lee, E. J.; Kwon, K. J.; Shin, C. Y.; Song, K.-H.; Park, J.-H.; Jo, I.; Han, S.-H. Troglitazone, a Thiazolidinedione, Decreases Tau Phosphorylation through the Inhibition of Cyclin-Dependent Kinase 5 Activity in SH-SY5Y Neuroblastoma Cells and Primary Neurons. J. Neurochem. 2013, 126 (5), 685695,  DOI: 10.1111/jnc.12264
    57. 57
      Harrington, C.; Sawchak, S.; Chiang, C.; Davies, J.; Donovan, C.; Saunders, A. M.; Irizarry, M.; Jeter, B.; Zvartau-Hind, M.; H. van Dyck, C.; Gold, M. Rosiglitazone Does Not Improve Cognition or Global Function When Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies. Curr. Alzheimer Res. 2011, 8 (5), 592606,  DOI: 10.2174/156720511796391935
    58. 58
      Gold, M.; Alderton, C.; Zvartau-Hind, M.; Egginton, S.; Saunders, A. M.; Irizarry, M.; Craft, S.; Landreth, G.; Linnamägi, Ü.; Sawchak, S. Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study. Dementia Geriatr. Cognit. Disord. 2010, 30 (2), 131146,  DOI: 10.1159/000318845
    59. 59
      Cheng, H.; Shang, Y.; Jiang, L.; Shi, T.-L.; Wang, L. The Peroxisome Proliferators Activated Receptor-Gamma Agonists as Therapeutics for the Treatment of Alzheimer’s Disease and Mild-to-Moderate Alzheimer’s Disease: A Meta-Analysis. Int. J. Neurosci. 2016, 126 (4), 299307,  DOI: 10.3109/00207454.2015.1015722
    60. 60
      Liu, J.; Wang, L.; Jia, J. Peroxisome Proliferator-Activated Receptor-Gamma Agonists for Alzheimer’s Disease and Amnestic Mild Cognitive Impairment: A Systematic Review and Meta-Analysis. Drugs Aging 2015, 32 (1), 5765,  DOI: 10.1007/s40266-014-0228-7
    61. 61
      Breidert, T.; Callebert, J.; Heneka, M. T.; Landreth, G.; Launay, J. M.; Hirsch, E. C. Protective Action of the Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone in a Mouse Model of Parkinson’s Disease. J. Neurochem. 2002, 82 (3), 615624,  DOI: 10.1046/j.1471-4159.2002.00990.x
    62. 62
      Quinn, L. P.; Crook, B.; Hows, M. E.; Vidgeon-Hart, M.; Chapman, H.; Upton, N.; Medhurst, A. D.; Virley, D. J. The PPARγ Agonist Pioglitazone Is Effective in the MPTP Mouse Model of Parkinson’s Disease through Inhibition of Monoamine Oxidase B. Br. J. Pharmacol. 2008, 154 (1), 226233,  DOI: 10.1038/bjp.2008.78
    63. 63
      Pisanu, A.; Lecca, D.; Mulas, G.; Wardas, J.; Simbula, G.; Spiga, S.; Carta, A. R. Dynamic Changes in Pro-and Anti-Inflammatory Cytokines in Microglia after PPAR-γ Agonist Neuroprotective Treatment in the MPTPp Mouse Model of Progressive Parkinson’s Disease. Neurobiol. Dis. 2014, 71, 280291,  DOI: 10.1016/j.nbd.2014.08.011
    64. 64
      Swanson, C. R.; Joers, V.; Bondarenko, V.; Brunner, K.; Simmons, H. A.; Ziegler, T. E.; Kemnitz, J. W.; Johnson, J. A.; Emborg, M. E. The PPAR-γ Agonist Pioglitazone Modulates Inflammation and Induces Neuroprotection in Parkinsonian Monkeys. J. Neuroinflammation 2011, 8, 91,  DOI: 10.1186/1742-2094-8-91
    65. 65
      Pinto, M.; Nissanka, N.; Peralta, S.; Brambilla, R.; Diaz, F.; Moraes, C. T. Pioglitazone Ameliorates the Phenotype of a Novel Parkinson’s Disease Mouse Model by Reducing Neuroinflammation. Mol. Neurodegener. 2016, 11, 25,  DOI: 10.1186/s13024-016-0090-7
    66. 66
      Lecca, D.; Nevin, D. K.; Mulas, G.; Casu, M. A.; Diana, A.; Rossi, D.; Sacchetti, G.; Carta, A. R. Neuroprotective and Anti-Inflammatory Properties of a Novel Non-Thiazolidinedione PPARγ Agonist in Vitro and in MPTP-Treated Mice. Neuroscience 2015, 302, 2335,  DOI: 10.1016/j.neuroscience.2015.04.026
    67. 67
      Lecca, D.; Janda, E.; Mulas, G.; Diana, A.; Martino, C.; Angius, F.; Spolitu, S.; Casu, M. A.; Simbula, G.; Boi, L.; Batetta, B.; Spiga, S.; Carta, A. R. Boosting Phagocytosis and Anti-Inflammatory Phenotype in Microglia Mediates Neuroprotection by PPARγ Agonist MDG548 in Parkinson’s Disease Models. Br. J. Pharmacol. 2018, 175 (16), 32983314,  DOI: 10.1111/bph.14214
    68. 68
      Swanson, C. R.; Du, E.; Johnson, D. A.; Johnson, J. A.; Emborg, M. E. Neuroprotective Properties of a Novel Non-Thiazoledinedione Partial PPAR-γ Agonist against MPTP. PPAR Res. 2013, 2013, 582809  DOI: 10.1155/2013/582809
    69. 69
      Das, N. R.; Gangwal, R. P.; Damre, M. V.; Sangamwar, A. T.; Sharma, S. S. A PPAR-β/δ Agonist Is Neuroprotective and Decreases Cognitive Impairment in a Rodent Model of Parkinson’s Disease. Curr. Neurovasc. Res. 2014, 11 (2), 114124,  DOI: 10.2174/1567202611666140318114037
    70. 70
      Uppalapati, D.; Das, N. R.; Gangwal, R. P.; Damre, M. V.; Sangamwar, A. T.; Sharma, S. S. Neuroprotective Potential of Peroxisome Proliferator Activated Receptor-α Agonist in Cognitive Impairment in Parkinson’s Disease: Behavioral, Biochemical, and PBPK Profile. PPAR Res. 2014, 2014, 753587,  DOI: 10.1155/2014/753587
    71. 71
      Barbiero, J. K.; Santiago, R.; Tonin, F. S.; Boschen, S.; Da Silva, L. M.; De Paula Werner, M. F.; Da Cunha, C.; Lima, M. M. S.; Vital, M. A. B. F. PPAR-α Agonist Fenofibrate Protects against the Damaging Effects of MPTP in a Rat Model of Parkinson’s Disease. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2014, 53, 3544,  DOI: 10.1016/j.pnpbp.2014.02.009
    72. 72
      Martin, H. L.; Mounsey, R. B.; Sathe, K.; Mustafa, S.; Nelson, M. C.; Evans, R. M.; Teismann, P. A Peroxisome Proliferator-Activated Receptor-δ Agonist Provides Neuroprotection in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson’s Disease. Neuroscience 2013, 240, 191203,  DOI: 10.1016/j.neuroscience.2013.02.058
    73. 73
      Lee, Y.; Cho, J.-H.; Lee, S.; Lee, W.; Chang, S.-C.; Chung, H. Y.; Moon, H. R.; Lee, J. Neuroprotective Effects of MHY908, a PPAR α/γ Dual Agonist, in a MPTP-Induced Parkinson’s Disease Model. Brain Res. 2019, 1704, 4758,  DOI: 10.1016/j.brainres.2018.09.036
    74. 74
      Chen, L.; Xue, L.; Zheng, J.; Tian, X.; Zhang, Y.; Tong, Q. PPARß/δ Agonist Alleviates NLRP3 Inflammasome-Mediated Neuroinflammation in the MPTP Mouse Model of Parkinson’s Disease. Behav. Brain Res. 2019, 356, 483489,  DOI: 10.1016/j.bbr.2018.06.005
    75. 75
      Mounsey, R. B.; Martin, H. L.; Nelson, M. C.; Evans, R. M.; Teismann, P. The Effect of Neuronal Conditional Knock-out of Peroxisome Proliferator-Activated Receptors in the MPTP Mouse Model of Parkinson’s Disease. Neuroscience 2015, 300, 576584,  DOI: 10.1016/j.neuroscience.2015.05.048
    76. 76
      Tong, Q.; Wu, L.; Gao, Q.; Ou, Z.; Zhu, D.; Zhang, Y. PPARβ/δ Agonist Provides Neuroprotection by Suppression of IRE1α–Caspase-12-Mediated Endoplasmic Reticulum Stress Pathway in the Rotenone Rat Model of Parkinson’s Disease. Mol. Neurobiol. 2016, 53 (8), 38223831,  DOI: 10.1007/s12035-015-9309-9
    77. 77
      Bonato, J. M.; Bassani, T. B.; Milani, H.; Vital, M. A. B. F.; de Oliveira, R. M. W. Pioglitazone Reduces Mortality, Prevents Depressive-like Behavior, and Impacts Hippocampal Neurogenesis in the 6-OHDA Model of Parkinson’s Disease in Rats. Exp. Neurol. 2018, 300, 188200,  DOI: 10.1016/j.expneurol.2017.11.009
    78. 78
      Machado, M. M. F.; Bassani, T. B.; Cóppola-Segovia, V.; Moura, E. L. R.; Zanata, S. M.; Andreatini, R.; Vital, M. A. B. F. PPAR-γ Agonist Pioglitazone Reduces Microglial Proliferation and NF-KB Activation in the Substantia Nigra in the 6-Hydroxydopamine Model of Parkinson’s Disease. Pharmacol. Rep. 2019, 71 (4), 556564,  DOI: 10.1016/j.pharep.2018.11.005
    79. 79
      Lee, E. Y.; Lee, J. E.; Park, J. H.; Shin, I. C.; Koh, H. C. Rosiglitazone, a PPAR-γ Agonist, Protects against Striatal Dopaminergic Neurodegeneration Induced by 6-OHDA Lesions in the Substantia Nigra of Rats. Toxicol. Lett. 2012, 213 (3), 332344,  DOI: 10.1016/j.toxlet.2012.07.016
    80. 80
      Martinez, A. A.; Morgese, M. G.; Pisanu, A.; Macheda, T.; Paquette, M. A.; Seillier, A.; Cassano, T.; Carta, A. R.; Giuffrida, A. Activation of PPAR Gamma Receptors Reduces Levodopa-Induced Dyskinesias in 6-OHDA-Lesioned Rats. Neurobiol. Dis. 2015, 74, 295304,  DOI: 10.1016/j.nbd.2014.11.024
    81. 81
      Gottschalk, C. G.; Roy, A.; Jana, M.; Kundu, M.; Pahan, K. Activation of Peroxisome Proliferator-Activated Receptor-α Increases the Expression of Nuclear Receptor Related 1 Protein (Nurr1) in Dopaminergic Neurons. Mol. Neurobiol. 2019, 56 (11), 78727887,  DOI: 10.1007/s12035-019-01649-y
    82. 82
      Brauer, R.; Bhaskaran, K.; Chaturvedi, N.; Dexter, D. T.; Smeeth, L.; Douglas, I. Glitazone Treatment and Incidence of Parkinson’s Disease among People with Diabetes: A Retrospective Cohort Study. PLoS Med. 2015, 12 (7), e1001854,  DOI: 10.1371/journal.pmed.1001854
    83. 83
      Mutez, E.; Duhamel, A.; Defebvre, L.; Bordet, R.; Destée, A.; Kreisler, A. Lipid-Lowering Drugs Are Associated with Delayed Onset and Slower Course of Parkinson’s Disease. Pharmacol. Res. 2009, 60 (1), 4145,  DOI: 10.1016/j.phrs.2009.03.010
    84. 84
      Szalardy, L.; Zadori, D.; Tanczos, E.; Simu, M.; Bencsik, K.; Vecsei, L.; Klivenyi, P. Elevated Levels of PPAR-Gamma in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Neurosci. Lett. 2013, 554, 131134,  DOI: 10.1016/j.neulet.2013.08.069
    85. 85
      Szalardy, L.; Zadori, D.; Bencsik, K.; Vecsei, L.; Klivenyi, P. Unlike PPARgamma, Neither Other PPARs nor PGC-1alpha Is Elevated in the Cerebrospinal Fluid of Patients with Multiple Sclerosis. Neurosci. Lett. 2017, 651, 128133,  DOI: 10.1016/j.neulet.2017.05.008
    86. 86
      Wouters, E.; Grajchen, E.; Jorissen, W.; Dierckx, T.; Wetzels, S.; Loix, M.; Tulleners, M. P.; Staels, B.; Stinissen, P.; Haidar, M.; Bogie, J. F. J.; Hendriks, J. J. A. Altered PPARγ Expression Promotes Myelin-Induced Foam Cell Formation in Macrophages in Multiple Sclerosis. Int. J. Mol. Sci. 2020, 21 (23), 9329,  DOI: 10.3390/ijms21239329
    87. 87
      Feinstein, D. L.; Galea, E.; Gavrilyuk, V.; Brosnan, C. F.; Whitacre, C. C.; Dumitrescu-Ozimek, L.; Landreth, G. E.; Pershadsingh, H. A.; Weinberg, G.; Heneka, M. T. Peroxisome Proliferator-Activated Receptor-γ Agonists Prevent Experimental Autoimmune Encephalomyelitis. Ann. Neurol. 2002, 51 (6), 694702,  DOI: 10.1002/ana.10206
    88. 88
      Klotz, L.; Burgdorf, S.; Dani, I.; Saijo, K.; Flossdorf, J.; Hucke, S.; Alferink, J.; Novak, N.; Beyer, M.; Mayer, G.; Langhans, B.; Klockgether, T.; Waisman, A.; Eberl, G.; Schultze, J.; Famulok, M.; Kolanus, W.; Glass, C.; Kurts, C.; Knolle, P. The Nuclear Receptor PPARγ Selectively Inhibits Th17 Differentiation in a T Cell–Intrinsic Fashion and Suppresses CNS Autoimmunity. J. Exp. Med. 2009, 206 (10), 20792089,  DOI: 10.1084/jem.20082771
    89. 89
      Chedrawe, M. A. J.; Holman, S. P.; Lamport, A.-C.; Akay, T.; Robertson, G. S. Pioglitazone Is Superior to Quetiapine, Clozapine and Tamoxifen at Alleviating Experimental Autoimmune Encephalomyelitis in Mice. J. Neuroimmunol. 2018, 321, 7282,  DOI: 10.1016/j.jneuroim.2018.06.001
    90. 90
      Diab, A.; Deng, C.; Smith, J. D.; Hussain, R. Z.; Phanavanh, B.; Lovett-Racke, A. E.; Drew, P. D.; Racke, M. K. Peroxisome Proliferator-Activated Receptor-γ Agonist 15-Deoxy-Δ12,1412,14-Prostaglandin J2 Ameliorates Experimental Autoimmune Encephalomyelitis. J. Immunol. 2002, 168 (5), 25082515,  DOI: 10.4049/jimmunol.168.5.2508
    91. 91
      Diab, A.; Hussain, R. Z.; Lovett-Racke, A. E.; Chavis, J. A.; Drew, P. D.; Racke, M. K. Ligands for the Peroxisome Proliferator-Activated Receptor-γ and the Retinoid X Receptor Exert Additive Anti-Inflammatory Effects on Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2004, 148 (1–2), 116126,  DOI: 10.1016/j.jneuroim.2003.11.010
    92. 92
      Bernardo, A.; Giammarco, M. L.; De Nuccio, C.; Ajmone-Cat, M. A.; Visentin, S.; De Simone, R.; Minghetti, L. Docosahexaenoic Acid Promotes Oligodendrocyte Differentiation via PPAR-γ Signalling and Prevents Tumor Necrosis Factor-α-Dependent Maturational Arrest. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2017, 1862 (9), 10131023,  DOI: 10.1016/j.bbalip.2017.06.014
    93. 93
      De Nuccio, C.; Bernardo, A.; Cruciani, C.; De Simone, R.; Visentin, S.; Minghetti, L. Peroxisome Proliferator Activated Receptor-γ Agonists Protect Oligodendrocyte Progenitors against Tumor Necrosis Factor-Alpha-Induced Damage: Effects on Mitochondrial Functions and Differentiation. Exp. Neurol. 2015, 271, 506514,  DOI: 10.1016/j.expneurol.2015.07.014
    94. 94
      Storer, P. D.; Xu, J.; Chavis, J.; Drew, P. D. Peroxisome Proliferator-Activated Receptor-Gamma Agonists Inhibit the Activation of Microglia and Astrocytes: Implications for Multiple Sclerosis. J. Neuroimmunol. 2005, 161 (1–2), 113122,  DOI: 10.1016/j.jneuroim.2004.12.015
    95. 95
      Zhang, F.; Liu, F.; Yan, M.; Ji, H.; Hu, L.; Li, X.; Qian, J.; He, X.; Zhang, L.; Shen, A.; Cheng, C. Peroxisome Proliferator-Activated Receptor-γ Agonists Suppress INOS Expression Induced by LPS in Rat Primary Schwann Cells. J. Neuroimmunol. 2010, 218 (1–2), 3647,  DOI: 10.1016/j.jneuroim.2009.10.016
    96. 96
      Grajchen, E.; Wouters, E.; Van De Haterd, B.; Haidar, M.; Hardonnière, K.; Dierckx, T.; Van Broeckhoven, J.; Erens, C.; Hendrix, S.; Kerdine-Römer, S.; Hendriks, J. J. A.; Bogie, J. F. J. CD36-Mediated Uptake of Myelin Debris by Macrophages and Microglia Reduces Neuroinflammation. J. Neuroinflammation 2020, 17, 224,  DOI: 10.1186/s12974-020-01899-x
    97. 97
      Schmidt, S.; Moric, E.; Schmidt, M.; Sastre, M.; Feinstein, D. L.; Heneka, M. T. Anti-Inflammatory and Antiproliferative Actions of PPAR-γ Agonists on T Lymphocytes Derived from MS Patients. J. Leukocyte Biol. 2004, 75 (3), 478485,  DOI: 10.1189/jlb.0803402
    98. 98
      Polak, P. E.; Kalinin, S.; Dello Russo, C.; Gavrilyuk, V.; Sharp, A.; Peters, J. M.; Richardson, J.; Willson, T. M.; Weinberg, G.; Feinstein, D. L. Protective Effects of a Peroxisome Proliferator-Activated Receptor-β/δ Agonist in Experimental Autoimmune Encephalomyelitis. J. Neuroimmunol. 2005, 168 (1–2), 6575,  DOI: 10.1016/j.jneuroim.2005.07.006
    99. 99
      Kanakasabai, S.; Walline, C. C.; Chakraborty, S.; Bright, J. J. PPARδ Deficient Mice Develop Elevated Th1/Th17 Responses and Prolonged Experimental Autoimmune Encephalomyelitis. Brain Res. 2011, 1376, 101112,  DOI: 10.1016/j.brainres.2010.12.059
    100. 100
      Defaux, A.; Zurich, M. G.; Braissant, O.; Honegger, P.; Monnet-Tschudi, F. Effects of the PPAR-β Agonist GW501516 in an in Vitro Model of Brain Inflammation and Antibody-Induced Demyelination. J. Neuroinflammation 2009, 6, 15,  DOI: 10.1186/1742-2094-6-15
    101. 101
      Kanakasabai, S.; Chearwae, W.; Walline, C. C.; Iams, W.; Adams, S. M.; Bright, J. J. Peroxisome Proliferator-Activated Receptor δ Agonists Inhibit T Helper Type 1 (Th1) and Th17 Responses in Experimental Allergic Encephalomyelitis. Immunology 2010, 130 (4), 572588,  DOI: 10.1111/j.1365-2567.2010.03261.x
    102. 102
      Jana, M.; Mondal, S.; Gonzalez, F. J.; Pahan, K. Gemfibrozil, a Lipid-Lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-Activated Receptor-β. J. Biol. Chem. 2012, 287 (41), 3413434148,  DOI: 10.1074/jbc.M112.398552
    103. 103
      Sakuma, S.; Endo, T.; Kanda, T.; Nakamura, H.; Yamasaki, S.; Yamakawa, T. Synthesis of a Novel Human PPARδ Selective Agonist and Its Stimulatory Effect on Oligodendrocyte Differentiation. Bioorg. Med. Chem. Lett. 2011, 21 (1), 240244,  DOI: 10.1016/j.bmcl.2010.11.030
    104. 104
      Kaiser, C. C.; Shukla, D. K.; Stebbins, G. T.; Skias, D. D.; Jeffery, D. R.; Stefoski, D.; Katsamakis, G.; Feinstein, D. L. A Pilot Test of Pioglitazone as an Add-on in Patients with Relapsing Remitting Multiple Sclerosis. J. Neuroimmunol. 2009, 211 (1–2), 124130,  DOI: 10.1016/j.jneuroim.2009.04.011
    105. 105
      Shukla, D. K.; Kaiser, C. C.; Stebbins, G. T.; Feinstein, D. L. Effects of Pioglitazone on Diffusion Tensor Imaging Indices in Multiple Sclerosis Patients. Neurosci. Lett. 2010, 472 (3), 153156,  DOI: 10.1016/j.neulet.2010.01.046
    106. 106
      Negrotto, L.; Farez, M. F.; Correale, J. Immunologic Effects of Metformin and Pioglitazone Treatment on Metabolic Syndrome and Multiple Sclerosis. JAMA Neurol. 2016, 73 (5), 520528,  DOI: 10.1001/jamaneurol.2015.4807
    107. 107
      Ratziu, V.; Harrison, S. A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S.; Drenth, J.; Anstee, Q. M.; Hum, D.; Hanf, R.; Roudot, A.; Megnien, S.; Staels, B.; Sanyal, A. Elafibranor, an Agonist of the Peroxisome Proliferator–Activated Receptor−α and – δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 2016, 150 (5), 11471159,  DOI: 10.1053/j.gastro.2016.01.038
    108. 108
      Henke, B. R.; Blanchard, S. G.; Brackeen, M. F.; Brown, K. K.; Cobb, J. E.; Collins, J. L.; Harrington, W. W.; Hashim, M. A.; Hull-Ryde, E. A.; Kaldor, I.; Kliewer, S. A.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J. M.; Lenhard, J. M.; Orband-Miller, L. A.; Miller, J. F.; Mook, R. A.; Noble, S. A.; Oliver, W.; Parks, D. J.; Plunket, K. D.; Szewczyk, J. R.; Willson, T. M. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 1. Discovery of a Novel Series of Potent Antihyperglycemic and Antihyperlipidemic Agents. J. Med. Chem. 1998, 41 (25), 50205036,  DOI: 10.1021/jm9804127
    109. 109
      Cobb, J. E.; Blanchard, S. G.; Boswell, E. G.; Brown, K. K.; Charifson, P. S.; Cooper, J. P.; Collins, J. L.; Dezube, M.; Henke, B. R.; Hull-Ryde, E. A.; Lake, D. H.; Lenhard, J. M.; Oliver, W.; Oplinger, J.; Pentti, M.; Parks, D. J.; Plunket, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 3. Structure-Activity Relationship and Optimization of the N-Aryl Substituent. J. Med. Chem. 1998, 41 (25), 50555069,  DOI: 10.1021/jm980414r
    110. 110
      Collins, J. L.; Blanchard, S. G.; Boswell, G. E.; Charifson, P. S.; Cobb, J. E.; Henke, B. R.; Hull-Ryde, E. A.; Kazmierski, W. M.; Lake, D. H.; Leesnitzer, L. M.; Lehmann, J.; Lenhard, J. M.; Orband-Miller, L. A.; Gray-Nunez, Y.; Parks, D. J.; Plunkett, K. D.; Tong, W.-Q. N-(2-Benzoylphenyl)-L-Tyrosine PPARγ Agonists. 2. Structure-Activity Relationship and Optimization of the Phenyl Alkyl Ether Moiety. J. Med. Chem. 1998, 41 (25), 50375054,  DOI: 10.1021/jm980413z
    111. 111
      Berger, J.; Leibowitz, M. D.; Doebber, T. W.; Elbrecht, A.; Zhang, B.; Zhou, G.; Biswas, C.; Cullinan, C. A.; Hayes, N. S.; Li, Y.; Tanen, M.; Ventre, J.; Wu, M. S.; Berger, G. D.; Mosley, R.; Marquis, R.; Santini, C.; Sahoo, S. P.; Tolman, R. L.; Smith, R. G.; M?ller, D. E. Novel Peroxisome Proliferator-Activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects. J. Biol. Chem. 1999, 274 (10), 67186725,  DOI: 10.1074/jbc.274.10.6718
    112. 112
      Brown, P. J.; Stuart, L. W.; Hurley, K. P.; Lewis, M. C.; Winegar, D. A.; Wilson, J. G.; Wilkison, W. O.; Ittoop, O. R.; Willson, T. M. Identification of a Subtype Selective Human PPARα Agonist through Parallel-Array Synthesis. Bioorg. Med. Chem. Lett. 2001, 11 (9), 12251227,  DOI: 10.1016/S0960-894X(01)00188-3
    113. 113
      Kane, C. D.; Stevens, K. A.; Fischer, J. E.; Haghpassand, M.; Royer, L. J.; Aldinger, C.; Landschulz, K. T.; Zagouras, P.; Bagley, S. W.; Hada, W.; Dullea, R.; Hayward, C. M.; Francone, O. L. Molecular Characterization of Novel and Selective Peroxisome Proliferator-Activated Receptor α Agonists with Robust Hypolipidemic Activity in Vivo. Mol. Pharmacol. 2009, 75 (2), 296306,  DOI: 10.1124/mol.108.051656
    114. 114
      Kuwabara, K.; Murakami, K.; Todo, M.; Aoki, T.; Asaki, T.; Murai, M.; Yano, J. A Novel Selective Peroxisome Proliferator-Activated Receptor α Agonist, 2-Methyl-c-5-[4-[5-Methyl-2-(4-Methylphenyl)-4-Oxazolyl]Butyl]-1, 3-Dioxane-r-2-Carboxylic Acid (NS-220), Potently Decreases Plasma Triglyceride and Glucose Levels and Modifies Lipopr. J. Pharmacol. Exp. Ther. 2004, 309 (3), 970977,  DOI: 10.1124/jpet.103.064659
    115. 115
      Santilli, A. A.; Scotese, A. C.; Tomarelli, R. M. A Potent Antihypercholesterolemic Agent: [4-Chloro-6-(2,3-Xylidino)-2-Pyrimidinylthio]Acetic Acid (Wy-14643). Experientia 1974, 30 (10), 11101111,  DOI: 10.1007/BF01923636
    116. 116
      Willson, T. M.; Brown, P. J.; Sternbach, D. D.; Henke, B. R. The PPARs: From Orphan Receptors to Drug Discovery. J. Med. Chem. 2000, 43, 527550,  DOI: 10.1021/jm990554g
    117. 117
      Pollinger, J.; Gellrich, L.; Schierle, S.; Kilu, W.; Schmidt, J.; Kalinowsky, L.; Ohrndorf, J.; Kaiser, A.; Heering, J.; Proschak, E.; Merk, D. Tuning Nuclear Receptor Selectivity of Wy14,643 towards Selective Retinoid X Receptor Modulation. J. Med. Chem. 2019, 62 (4), 21122126,  DOI: 10.1021/acs.jmedchem.8b01848
    118. 118
      Willson, T. M.; Cobb, J. E.; Cowan, D. J.; Wiethe, R. W.; Correa, I. D.; Prakash, S. R.; Beck, K. D.; Moore, L. B.; Kliewer, S. A.; Lehmann, J. M. The Structure-Activity Relationship between Peroxisome Proliferator-Activated Receptor γ Agonism and the Antihyperglycemic Activity of Thiazolidinediones. J. Med. Chem. 1996, 39 (3), 665668,  DOI: 10.1021/jm950395a
    119. 119
      Lehmann, J. M.; Moore, L. B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A. An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-Activated Receptor γ (PPARγ). J. Biol. Chem. 1995, 270 (22), 1295312956,  DOI: 10.1074/jbc.270.22.12953
    120. 120
      Brown, K. K.; Henke, B. R.; Blanchard, S. G.; Cobb, J. E.; Mook, R.; Kaldor, I.; Kliewer, S. A.; Lehmann, J. M.; Lenhard, J. M.; Harrington, W. W.; Novak, P. J.; Faison, W.; Binz, J. G.; Hashim, M. A.; Oliver, W. O.; Brown, H. R.; Parks, D. J.; Plunket, K. D.; Tong, W. Q.; Menius, J. A.; Adkison, K.; Noble, S. A.; Willson, T. M. A Novel N-Aryl Tyrosine Activator of Peroxisome Proliferator-Activated Receptor-γ Reverses the Diabetic Phenotype of the Zucker Diabetic Fatty Rat. Diabetes 1999, 48 (7), 14151424,  DOI: 10.2337/diabetes.48.7.1415
    121. 121
      Hanke, T.; Cheung, S.-Y.; Kilu, W.; Heering, J.; Ni, X.; Planz, V.; Schierle, S.; Faudone, G.; Friedrich, M.; Wanior, M.; Werz, O.; Windbergs, M.; Proschak, E.; Schubert-Zsilavecz, M.; Chaikuad, A.; Knapp, S.; Merk, D. A Selective Modulator of Peroxisome Proliferator-Activated Receptor γ with an Unprecedented Binding Mode. J. Med. Chem. 2020, 63 (9), 45554561,  DOI: 10.1021/acs.jmedchem.9b01786
    122. 122
      Leesnitzer, L. M.; Parks, D. J.; Bledsoe, R. K.; Cobb, J. E.; Collins, J. L.; Consler, T. G.; Davis, R. G.; Hull-Ryde, E. A.; Lenhard, J. M.; Patel, L.; Plunket, K. D.; Shenk, J. L.; Stimmel, J. B.; Therapontos, C.; Willson, T. M.; Blanchard, S. G. Functional Consequences of Cysteine Modification in the Ligand Binding Sites of Peroxisome Proliferator Activated Receptors by GW9662. Biochemistry 2002, 41 (21), 66406650,  DOI: 10.1021/bi0159581
    123. 123
      Oliver, W. R.; Shenk, J. L.; Snaith, M. R.; Russell, C. S.; Plunket, K. D.; Bodkin, N. L.; Lewis, M. C.; Winegar, D. A.; Sznaidman, M. L.; Lambert, M. H.; Xu, H. E.; Sternbach, D. D.; Kliewer, S. A.; Hansen, B. C.; Willson, T. M. A Selective Peroxisome Proliferator-Activated Receptor δ Agonist Promotes Reverse Cholesterol Transport. Proc. Natl. Acad. Sci. U. S. A. 2001, 98 (9), 53065311,  DOI: 10.1073/pnas.091021198
    124. 124
      Sznaidman, M. L.; Haffner, C. D.; Maloney, P. R.; Fivush, A.; Chao, E.; Goreham, D.; Sierra, M. L.; LeGrumelec, C.; Xu, H. E.; Montana, V. G.; Lambert, M. H.; Willson, T. M.; Oliver, W. R.; Sternbach, D. D. Novel Selective Small Molecule Agonists for Peroxisome Proliferator-Activated Receptor δ (PPARδ) - Synthesis and Biological Activity. Bioorg. Med. Chem. Lett. 2003, 13 (9), 15171521,  DOI: 10.1016/S0960-894X(03)00207-5
    125. 125
      Zhang, R.; Wang, A.; DeAngelis, A.; Pelton, P.; Xu, J.; Zhu, P.; Zhou, L.; Demarest, K.; Murray, W. V.; Kuo, G.-H. Discovery of Para-Alkylthiophenoxyacetic Acids as a Novel Series of Potent and Selective PPARδ Agonists. Bioorg. Med. Chem. Lett. 2007, 17 (14), 38553859,  DOI: 10.1016/j.bmcl.2007.05.007
    126. 126
      Chang, K. L.; Pee, H. N.; Yang, S.; Ho, P. C. Influence of Drug Transporters and Stereoselectivity on the Brain Penetration of Pioglitazone as a Potential Medicine against Alzheimer’s Disease. Sci. Rep. 2015, 5, 9000,  DOI: 10.1038/srep09000
    127. 127
      Sime, M.; Allan, A. C.; Chapman, P.; Fieldhouse, C.; Giblin, G. M. P.; Healy, M. P.; Lambert, M. H.; Leesnitzer, L. M.; Lewis, A.; Merrihew, R. V.; Rutter, R. A.; Sasse, R.; Shearer, B. G.; Willson, T. M.; Xu, R. X.; Virley, D. J. Discovery of GSK1997132B a Novel Centrally Penetrant Benzimidazole PPARγ Partial Agonist. Bioorg. Med. Chem. Lett. 2011, 21 (18), 55685572,  DOI: 10.1016/j.bmcl.2011.06.088
    128. 128
      Uriz-Huarte, A.; Date, A.; Ang, H.; Ali, S.; Brady, H. J. M.; Fuchter, M. J. The Transcriptional Repressor REV-ERB as a Novel Target for Disease. Bioorg. Med. Chem. Lett. 2020, 30 (17), 127395,  DOI: 10.1016/j.bmcl.2020.127395
    129. 129
      Kojetin, D. J.; Burris, T. P. REV-ERB and ROR Nuclear Receptors as Drug Targets. Nat. Rev. Drug Discovery 2014, 13 (3), 197216,  DOI: 10.1038/nrd4100
    130. 130
      Chang, C.; Loo, C.-S.; Zhao, X.; Solt, L. A.; Liang, Y.; Bapat, S. P.; Cho, H.; Kamenecka, T. M.; Leblanc, M.; Atkins, A. R.; Yu, R. T.; Downes, M.; Burris, T. P.; Evans, R. M.; Zheng, Y. The Nuclear Receptor REV-ERBα Modulates Th17 Cell-Mediated Autoimmune Disease. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (37), 1852818536,  DOI: 10.1073/pnas.1907563116
    131. 131
      Lazar, M. A.; Hodin, R. A.; Darling, D. S.; Chin, W. W. A Novel Member of the Thyroid/Steroid Hormone Receptor Family Is Encoded by the Opposite Strand of the Rat c-ErbA Alpha Transcriptional Unit. Mol. Cell. Biol. 1989, 9 (3), 11281136,  DOI: 10.1128/MCB.9.3.1128
    132. 132
      Forman, B. M.; Chen, J.; Blumberg, B.; Kliewer, S. A.; Henshaw, R.; Ong, E. S.; Evans, R. M. Cross-Talk among ROR Alpha 1 and the Rev-Erb Family of Orphan Nuclear Receptors. Mol. Endocrinol. 1994, 8 (9), 12531261,  DOI: 10.1210/mend.8.9.7838158
    133. 133
      Dumas, B.; Harding, H. P.; Choi, H. S.; Lehmann, K. A.; Chung, M.; Lazar, M. A.; Moore, D. D. A New Orphan Member of the Nuclear Hormone Receptor Superfamily Closely Related to Rev-Erb. Mol. Endocrinol. 1994, 8 (8), 9961005,  DOI: 10.1210/mend.8.8.7997240
    134. 134
      Yin, L.; Lazar, M. A. The Orphan Nuclear Receptor Rev-Erbα Recruits the N-CoR/Histone Deacetylase 3 Corepressor to Regulate the Circadian Bmal1 Gene. Mol. Endocrinol. 2005, 19 (6), 14521459,  DOI: 10.1210/me.2005-0057
    135. 135
      Torra, I. P.; Tsibulsky, V.; Delaunay, F.; Saladin, R.; Laudet, V.; Fruchart, J.-C.; Kosykh, V.; Staels, B. Circadian and Glucocorticoid Regulation of Rev-Erbα Expression in Liver. Endocrinology 2000, 141 (10), 37993806,  DOI: 10.1210/endo.141.10.7708
    136. 136
      Balsalobre, A.; Damiola, F.; Schibler, U. A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells. Cell 1998, 93 (6), 929937,  DOI: 10.1016/S0092-8674(00)81199-X
    137. 137
      Wolff, S. E. C.; Wang, X.-L.; Jiao, H.; Sun, J.; Kalsbeek, A.; Yi, C.-X.; Gao, Y. The Effect of Rev-Erbα Agonist SR9011 on the Immune Response and Cell Metabolism of Microglia. Front. Immunol. 2020, 11, 550145,  DOI: 10.3389/fimmu.2020.550145
    138. 138
      Guo, D.; Zhu, Y.; Sun, H.; Xu, X.; Zhang, S.; Hao, Z.; Wang, G.; Mu, C.; Ren, H. Pharmacological Activation of REV-ERBα Represses LPS-Induced Microglial Activation through the NF-KB Pathway. Acta Pharmacol. Sin. 2019, 40 (1), 2634,  DOI: 10.1038/s41401-018-0064-0
    139. 139
      Roby, D. A.; Ruiz, F.; Kermath, B. A.; Voorhees, J. R.; Niehoff, M.; Zhang, J.; Morley, J. E.; Musiek, E. S.; Farr, S. A.; Burris, T. P. Pharmacological Activation of the Nuclear Receptor REV-ERB Reverses Cognitive Deficits and Reduces Amyloid-β Burden in a Mouse Model of Alzheimer’s Disease. PLoS One 2019, 14 (4), e0215004,  DOI: 10.1371/journal.pone.0215004
    140. 140
      Griffin, P.; Dimitry, J. M.; Sheehan, P. W.; Lananna, B. V.; Guo, C.; Robinette, M. L.; Hayes, M. E.; Cedeño, M. R.; Nadarajah, C. J.; Ezerskiy, L. A.; Colonna, M.; Zhang, J.; Bauer, A. Q.; Burris, T. P.; Musiek, E. S. Circadian Clock Protein Rev-Erbα Regulates Neuroinflammation. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (11), 51025107,  DOI: 10.1073/pnas.1812405116
    141. 141
      Lee, J.; Kim, D. E.; Griffin, P.; Sheehan, P. W.; Kim, D.-H.; Musiek, E. S.; Yoon, S.-Y. Inhibition of REV-ERBs Stimulates Microglial Amyloid-Beta Clearance and Reduces Amyloid Plaque Deposition in the 5XFAD Mouse Model of Alzheimer’s Disease. Aging Cell 2020, 19 (2), e13078,  DOI: 10.1111/acel.13078
    142. 142
      Raghuram, S.; Stayrook, K. R.; Huang, P.; Rogers, P. M.; Nosie, A. K.; McClure, D. B.; Burris, L. L.; Khorasanizadeh, S.; Burris, T. P.; Rastinejad, F. Identification of Heme as the Ligand for the Orphan Nuclear Receptors REV-ERBα and REV-ERBβ. Nat. Struct. Mol. Biol. 2007, 14 (12), 12071213,  DOI: 10.1038/nsmb1344
    143. 143
      Trump, R. P.; Bresciani, S.; Cooper, A. W. J.; Tellam, J. P.; Wojno, J.; Blaikley, J.; Orband-Miller, L. A.; Kashatus, J. A.; Boudjelal, M.; Dawson, H. C.; Loudon, A.; Ray, D.; Grant, D.; Farrow, S. N.; Willson, T. M.; Tomkinson, N. C. O. Optimized Chemical Probes for REV-ERBα. J. Med. Chem. 2013, 56 (11), 47294737,  DOI: 10.1021/jm400458q
    144. 144
      Noel, R.; Song, X.; Shin, Y.; Banerjee, S.; Kojetin, D.; Lin, L.; Ruiz, C. H.; Cameron, M. D.; Burris, T. P.; Kamenecka, T. M. Synthesis and SAR of Tetrahydroisoquinolines as Rev-Erbα Agonists. Bioorg. Med. Chem. Lett. 2012, 22 (11), 37393742,  DOI: 10.1016/j.bmcl.2012.04.023
    145. 145
      Westermaier, Y.; Ruiz-Carmona, S.; Theret, I.; Perron-Sierra, F.; Poissonnet, G.; Dacquet, C.; Boutin, J. A.; Ducrot, P.; Barril, X. Binding Mode Prediction and MD/MMPBSA-Based Free Energy Ranking for Agonists of REV-ERBα/NCoR. J. Comput.-Aided Mol. Des. 2017, 31 (8), 755775,  DOI: 10.1007/s10822-017-0040-7
    146. 146
      Kojetin, D.; Wang, Y.; Kamenecka, T. M.; Burris, T. P. Identification of SR8278, a Synthetic Antagonist of the Nuclear Heme Receptor REV-ERB. ACS Chem. Biol. 2011, 6 (2), 131134,  DOI: 10.1021/cb1002575
    147. 147
      De Mei, C; Ercolani, L; Parodi, C; Veronesi, M; Vecchio, C L.; Bottegoni, G; Torrente, E; Scarpelli, R; Marotta, R; Ruffili, R; Mattioli, M; Reggiani, A; Wade, M; Grimaldi, B Dual Inhibition of REV-ERBβ and Autophagy as a Novel Pharmacological Approach to Induce Cytotoxicity in Cancer Cells. Oncogene 2015, 34 (20), 25972608,  DOI: 10.1038/onc.2014.203
    148. 148
      Torrente, E.; Parodi, C.; Ercolani, L.; De Mei, C.; Ferrari, A.; Scarpelli, R.; Grimaldi, B. Synthesis and in Vitro Anticancer Activity of the First Class of Dual Inhibitors of REV-ERBβ and Autophagy. J. Med. Chem. 2015, 58 (15), 59005915,  DOI: 10.1021/acs.jmedchem.5b00511
    149. 149
      Dierickx, P.; Emmett, M. J.; Jiang, C.; Uehara, K.; Liu, M.; Adlanmerini, M.; Lazar, M. A. SR9009 Has REV-ERB–Independent Effects on Cell Proliferation and Metabolism. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (25), 1214712152,  DOI: 10.1073/pnas.1904226116
    150. 150
      Moore, D. D.; Kato, S.; Xie, W.; Mangelsdorf, D. J.; Schmidt, D. R.; Xiao, R.; Kliewer, S. A. International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor α, Farnesoid X Receptor β, Liver X Receptor α, Liver X Receptor β, and Vitamin D Receptor. Pharmacol. Rev. 2006, 58 (4), 742759,  DOI: 10.1124/pr.58.4.6
    151. 151
      Viennois, E.; Mouzat, K.; Dufour, J.; Morel, L.; Lobaccaro, J.-M.; Baron, S. Selective Liver X Receptor Modulators (SLiMs): What Use in Human Health?. Mol. Cell. Endocrinol. 2012, 351 (2), 129141,  DOI: 10.1016/j.mce.2011.08.036
    152. 152
      Mouzat, K.; Chudinova, A.; Polge, A.; Kantar, J.; Camu, W.; Raoul, C.; Lumbroso, S. Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?. Int. J. Mol. Sci. 2019, 20 (16), 3858,  DOI: 10.3390/ijms20163858
    153. 153
      Hong, C.; Tontonoz, P. Liver X Receptors in Lipid Metabolism: Opportunities for Drug Discovery. Nature Reviews Drug Discovery 2014, 13, 433444,  DOI: 10.1038/nrd4280
    154. 154
      Sodhi, R. K.; Singh, N. Liver X Receptors: Emerging Therapeutic Targets for Alzheimer’s Disease. Pharmacol Res. 2013, 72, 4551,  DOI: 10.1016/j.phrs.2013.03.008
    155. 155
      Moutinho, M.; Landreth, G. E. Therapeutic Potential of Nuclear Receptor Agonists in Alzheimer’s Disease. J. Lipid Res. 2017, 58 (10), 19371949,  DOI: 10.1194/jlr.R075556
    156. 156
      Björkhem, I.; Meaney, S. Brain Cholesterol: Long Secret Life behind a Barrier. Arterioscler., Thromb., Vasc. Biol. 2004, 24 (5), 806815,  DOI: 10.1161/01.ATV.0000120374.59826.1b
    157. 157
      Hussain, G.; Wang, J.; Rasul, A.; Anwar, H.; Imran, A.; Qasim, M.; Zafar, S.; Kamran, S. K. S.; Razzaq, A.; Aziz, N.; Ahmad, W.; Shabbir, A.; Iqbal, J.; Baig, S. M.; Sun, T. Role of Cholesterol and Sphingolipids in Brain Development and Neurological Diseases. Lipids in Health and Disease 2019, 18, 26,  DOI: 10.1186/s12944-019-0965-z
    158. 158
      Mauch, D. H.; Nägler, K.; Schumacher, S.; Göritz, C.; Müller, E.-C.; Otto, A.; Pfrieger, F. W. CNS Synaptogenesis Promoted by Glia-Derived Cholesterol. Science 2001, 294 (5545), 13541357,  DOI: 10.1126/science.294.5545.1354
    159. 159
      Zhang, J.; Liu, Q. Cholesterol Metabolism and Homeostasis in the Brain. Protein Cell 2015, 6 (4), 254264,  DOI: 10.1007/s13238-014-0131-3
    160. 160
      Abildayeva, K.; Jansen, P. J.; Hirsch-Reinshagen, V.; Bloks, V. W.; Bakker, A. H. F.; Ramaekers, F. C. S.; De Vente, J.; Groen, A. K.; Wellington, C. L.; Kuipers, F.; Mulder, M. 24(S)-Hydroxycholesterol Participates in a Liver X Receptor-Controlled Pathway in Astrocytes That Regulates Apolipoprotein E-Mediated Cholesterol Efflux. J. Biol. Chem. 2006, 281 (18), 1279912808,  DOI: 10.1074/jbc.M601019200
    161. 161
      Peet, D. J.; Turley, S. D.; Ma, W.; Janowski, B. A.; Lobaccaro, J. M. A.; Hammer, R. E.; Mangelsdorf, D. J. Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXRα. Cell 1998, 93 (5), 693704,  DOI: 10.1016/S0092-8674(00)81432-4
    162. 162
      Andersson, S.; Gustafsson, N.; Warner, M.; Gustafsson, J.-Å. Inactivation of Liver X Receptor β Leads to Adult-Onset Motor Neuron Degeneration in Male Mice. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (10), 38573862,  DOI: 10.1073/pnas.0500634102
    163. 163
      Bigini, P.; Steffensen, K. R.; Ferrario, A.; Diomede, L.; Ferrara, G.; Barbera, S.; Salzano, S.; Fumagalli, E.; Ghezzi, P.; Mennini, T.; Gustafsson, J.-Å. Neuropathologic and Biochemical Changes During Disease Progression in Liver X Receptor β –/– Mice, A Model of Adult Neuron Disease. J. Neuropathol. Exp. Neurol. 2010, 69 (6), 593605,  DOI: 10.1097/NEN.0b013e3181df20e1
    164. 164
      Meffre, D.; Shackleford, G.; Hichor, M.; Gorgievski, V.; Tzavara, E. T.; Trousson, A.; Ghoumari, A. M.; Deboux, C.; Oumesmar, B. N.; Liere, P.; Schumacher, M.; Baulieu, E.-E.; Charbonnier, F.; Grenier, J.; Massaad, C. Liver X Receptors Alpha and Beta Promote Myelination and Remyelination in the Cerebellum. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (24), 75877592,  DOI: 10.1073/pnas.1424951112
    165. 165
      Song, X.-Y.; Wu, W.-F.; Gabbi, C.; Dai, Y.-B.; So, M.; Chaurasiya, S. P.; Wang, L.; Warner, M.; Gustafsson, J. Å. Retinal and Optic Nerve Degeneration in Liver X Receptor β Knockout Mice. Proc. Natl. Acad. Sci. U. S. A. 2019, 116 (33), 1650716512,  DOI: 10.1073/pnas.1904719116
    166. 166
      Zelcer, N.; Khanlou, N.; Clare, R.; Jiang, Q.; Reed-Geaghan, E. G.; Landreth, G. E.; Vinters, H. V.; Tontonoz, P. Attenuation of Neuroinflammation and Alzheimer’s Disease Pathology by Liver x Receptors. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (25), 1060110606,  DOI: 10.1073/pnas.0701096104
    167. 167
      Cui, W.; Sun, Y.; Wang, Z.; Xu, C.; Peng, Y.; Li, R. Liver X Receptor Activation Attenuates Inflammatory Response and Protects Cholinergic Neurons in APP/PS1 Transgenic Mice. Neuroscience 2012, 210, 200210,  DOI: 10.1016/j.neuroscience.2012.02.047
    168. 168
      Strittmatter, W. J.; Saunders, A. M.; Schmechel, D.; Pericak-Vance, M.; Enghild, J.; Salvesen, G. S.; Roses, A. D. Apolipoprotein E: High-Avidity Binding to β-Amyloid and Increased Frequency of Type 4 Allele in Late-Onset Familial Alzheimer Disease. Proc. Natl. Acad. Sci. U. S. A. 1993, 90 (5), 19771981,  DOI: 10.1073/pnas.90.5.1977
    169. 169
      Pitas, R. E.; Boyles, J. K.; Lee, S. H.; Foss, D.; Mahley, R. W. Astrocytes Synthesize Apolipoprotein E and Metabolize Apolipoprotein E-Containing Lipoproteins. Biochim. Biophys. Acta, Lipids Lipid Metab. 1987, 917 (1), 148161,  DOI: 10.1016/0005-2760(87)90295-5
    170. 170
      Ignatius, M. J.; Gebicke-Harter, P. J.; Skene, J. H.; Schilling, J. W.; Weisgraber, K. H.; Mahley, R. W.; Shooter, E. M. Expression of Apolipoprotein E during Nerve Degeneration and Regeneration. Proc. Natl. Acad. Sci. U. S. A. 1986, 83 (4), 11251129,  DOI: 10.1073/pnas.83.4.1125
    171. 171
      Fukumoto, H.; Deng, A.; Irizarry, M. C.; Fitzgerald, M. L.; Rebeck, G. W. Induction of the Cholesterol Transporter ABCA1 in Central Nervous System Cells by Liver X Receptor Agonists Increases Secreted Aβ Levels. J. Biol. Chem. 2002, 277 (50), 4850848513,  DOI: 10.1074/jbc.M209085200
    172. 172
      Sun, Y.; Yao, J.; Kim, T.-W.; Tall, A. R. Expression of Liver X Receptor Target Genes Decreases Cellular Amyloid β Peptide Secretion. J. Biol. Chem. 2003, 278 (30), 2768827694,  DOI: 10.1074/jbc.M300760200
    173. 173
      Koldamova, R. P.; Lefterov, I. M.; Staufenbiel, M.; Wolfe, D.; Huang, S.; Glorioso, J. C.; Walter, M.; Roth, M. G.; Lazo, J. S. The Liver X Receptor Ligand T0901317 Decreases Amyloid β Production in Vitro and in a Mouse Model of Alzheimer’s Disease. J. Biol. Chem. 2005, 280 (6), 40794088,  DOI: 10.1074/jbc.M411420200
    174. 174
      Fitz, N. F.; Cronican, A.; Pham, T.; Fogg, A.; Fauq, A. H.; Chapman, R.; Lefterov, I.; Koldamova, R. Liver X Receptor Agonist Treatment Ameliorates Amyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23 Mice. J. Neurosci. 2010, 30 (20), 68626872,  DOI: 10.1523/JNEUROSCI.1051-10.2010
    175. 175
      Cui, W.; Sun, Y.; Wang, Z.; Xu, C.; Xu, L.; Wang, F.; Chen, Z.; Peng, Y.; Li, R. Activation of Liver x Receptor Decreases BACE1 Expression and Activity by Reducing Membrane Cholesterol Levels. Neurochem. Res. 2011, 36 (10), 19101921,  DOI: 10.1007/s11064-011-0513-3
    176. 176
      Wang, Q.; Wang, S.; Shi, Y.; Yao, M.; Hou, L.; Jiang, L. Reduction of Liver X Receptor β Expression in Primary Rat Neurons by Antisense Oligodeoxynucleotides Decreases Secreted Amyloid β Levels. Neurosci. Lett. 2014, 561, 146150,  DOI: 10.1016/j.neulet.2013.12.055
    177. 177
      Vanmierlo, T.; Rutten, K.; Dederen, J.; Bloks, V. W.; van Vark-van der Zee, L. C.; Kuipers, F.; Kiliaan, A.; Blokland, A.; Sijbrands, E. J. G.; Steinbusch, H.; Prickaerts, J.; Lütjohann, D.; Mulder, M. Liver X Receptor Activation Restores Memory in Aged AD Mice without Reducing Amyloid. Neurobiol. Aging 2011, 32 (7), 12621272,  DOI: 10.1016/j.neurobiolaging.2009.07.005
    178. 178
      Sandoval-Hernández, A. G.; Buitrago, L.; Moreno, H.; Cardona-Gómez, G. P.; Arboleda, G. Role of Liver X Receptor in AD Pathophysiology. PLoS One 2015, 10 (12), e0145467,  DOI: 10.1371/journal.pone.0145467
    179. 179
      Báez-Becerra, C.; Filipello, F.; Sandoval-Hernández, A.; Arboleda, H.; Arboleda, G. Liver X Receptor Agonist GW3965 Regulates Synaptic Function upon Amyloid Beta Exposure in Hippocampal Neurons. Neurotoxic. Res. 2018, 33 (4), 569579,  DOI: 10.1007/s12640-017-9845-3
    180. 180
      Kumar, N.; Solt, L. A.; Conkright, J. J.; Wang, Y.; Istrate, M. A.; Busby, S. A.; Garcia-Ordonez, R. D.; Burris, T. P.; Griffin, P. R. The Benzenesulfoamide T0901317 [N-(2,2,2-Trifluoroethyl)-N-[4-[2,2,2- Trifluoro-1-Hydroxy-1-(Trifluoromethyl)Ethyl]Phenyl]-Benzenesulfonamide] Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-α/γ Inverse Agonist. Mol. Pharmacol. 2010, 77 (2), 228236,  DOI: 10.1124/mol.109.060905
    181. 181
      Dai, Y.-B.; Tan, X.-J.; Wu, W.-F.; Warner, M.; Gustafsson, J.-Å. Liver X Receptor β Protects Dopaminergic Neurons in a Mouse Model of Parkinson Disease. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (32), 1311213117,  DOI: 10.1073/pnas.1210833109
    182. 182
      Nelissen, K.; Mulder, M.; Smets, I.; Timmermans, S.; Smeets, K.; Ameloot, M.; Hendriks, J. J. A. Liver X Receptors Regulate Cholesterol Homeostasis in Oligodendrocytes. J. Neurosci. Res. 2012, 90 (1), 6071,  DOI: 10.1002/jnr.22743
    183. 183
      Berghoff, S. A.; Spieth, L.; Sun, T.; Hosang, L.; Schlaphoff, L.; Depp, C.; Düking, T.; Winchenbach, J.; Neuber, J.; Ewers, D.; Scholz, P.; van der Meer, F.; Cantuti-Castelvetri, L.; Sasmita, A. O.; Meschkat, M.; Ruhwedel, T.; Möbius, W.; Sankowski, R.; Prinz, M.; Huitinga, I.; Sereda, M. W.; Odoardi, F.; Ischebeck, T.; Simons, M.; Stadelmann-Nessler, C.; Edgar, J. M.; Nave, K.-A.; Saher, G. Microglia Facilitate Repair of Demyelinated Lesions via Post-Squalene Sterol Synthesis. Nat. Neurosci. 2021, 24 (1), 4760,  DOI: 10.1038/s41593-020-00757-6
    184. 184
      Mailleux, J.; Vanmierlo, T.; Bogie, J. F. J.; Wouters, E.; Lütjohann, D.; Hendriks, J. J. A.; van Horssen, J. Active Liver X Receptor Signaling in Phagocytes in Multiple Sclerosis Lesions. Mult. Scler. J. 2018, 24 (3), 279289,  DOI: 10.1177/1352458517696595
    185. 185
      Cui, G.; Qin, X.; Wu, L.; Zhang, Y.; Sheng, X.; Yu, Q.; Sheng, H.; Xi, B.; Zhang, J. Z.; Zang, Y. Q. Liver X Receptor (LXR) Mediates Negative Regulation of Mouse and Human Th17 Differentiation. J. Clin. Invest. 2011, 121 (2), 658670,  DOI: 10.1172/JCI42974
    186. 186
      Schultz, J. R.; Tu, H.; Luk, A.; Repa, J. J.; Medina, J. C.; Li, L.; Schwendner, S.; Wang, S.; Thoolen, M.; Mangelsdorf, D. J.; Lustig, K. D.; Shan, B. Role of LXRs in Control of Lipogenesis. Genes Dev. 2000, 14 (22), 28312838,  DOI: 10.1101/gad.850400
    187. 187
      Collins, J. L.; Fivush, A. M.; Watson, M. A.; Galardi, C. M.; Lewis, M. C.; Moore, L. B.; Parks, D. J.; Wilson, J. G.; Tippin, T. K.; Binz, J. G.; Plunket, K. D.; Morgan, D. G.; Beaudet, E. J.; Whitney, K. D.; Kliewer, S. A.; Willson, T. M. Identification of a Nonsteroidal Liver X Receptor Agonist through Parallel Array Synthesis of Tertiary Amines. J. Med. Chem. 2002, 45 (10), 19631966,  DOI: 10.1021/jm0255116
    188. 188
      Kirchgessner, T. G.; Martin, R.; Sleph, P.; Grimm, D.; Liu, X.; Lupisella, J.; Smalley, J.; Narayanan, R.; Xie, Y.; Ostrowski, J.; Cantor, G. H.; Mohan, R.; Kick, E. Pharmacological Characterization of a Novel Liver X Receptor Agonist with Partial LXRα Activity and a Favorable Window in Nonhuman Primates. J. Pharmacol. Exp. Ther. 2015, 352 (2), 305314,  DOI: 10.1124/jpet.114.219923
    189. 189
      Wrobel, J.; Steffan, R.; Bowen, S. M.; Magolda, R.; Matelan, E.; Unwalla, R.; Basso, M.; Clerin, V.; Gardell, S. J.; Nambi, P.; Quinet, E.; Reminick, J. I.; Vlasuk, G. P.; Wang, S.; Feingold, I.; Huselton, C.; Bonn, T.; Farnegardh, M.; Hansson, T.; Nilsson, A. G.; Wilhelmsson, A.; Zamaratski, E.; Evans, M. J. Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride Synthesis. J. Med. Chem. 2008, 51 (22), 71617168,  DOI: 10.1021/jm800799q
    190. 190
      Stachel, S. J.; Zerbinatti, C.; Rudd, M. T.; Cosden, M.; Suon, S.; Nanda, K. K.; Wessner, K.; Dimuzio, J.; Maxwell, J.; Wu, Z.; Uslaner, J. M.; Michener, M. S.; Szczerba, P.; Brnardic, E.; Rada, V.; Kim, Y.; Meissner, R.; Wuelfing, P.; Yuan, Y.; Ballard, J.; Holahan, M.; Klein, D. J.; Lu, J.; Fradera, X.; Parthasarathy, G.; Uebele, V. N.; Chen, Z.; Li, Y.; Li, J.; Cooke, A. J.; Bennett, D. J.; Bilodeau, M. T.; Renger, J. Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease. J. Med. Chem. 2016, 59 (7), 34893498,  DOI: 10.1021/acs.jmedchem.6b00176
    191. 191
      Gezen-Ak, D.; Dursun, E. Molecular Basis of Vitamin D Action in Neurodegeneration: The Story of a Team Perspective. Hormones 2019, 18 (3), 1721,  DOI: 10.1007/s42000-018-0087-4
    192. 192
      Makishima, M.; Lu, T. T.; Xie, W.; Whitfield, G. K.; Domoto, H.; Evans, R. M.; Haussler, M. R.; Mangelsdorf, D. J. Vitamin D Receptor as an Intestinal Bile Acid Sensor. Science 2002, 296 (5571), 13131316,  DOI: 10.1126/science.1070477
    193. 193
      Yao, B.; He, J.; Yin, X.; Shi, Y.; Wan, J.; Tian, Z. The Protective Effect of Lithocholic Acid on the Intestinal Epithelial Barrier Is Mediated by the Vitamin D Receptor via a SIRT1/Nrf2 and NF-KB Dependent Mechanism in Caco-2 Cells. Toxicol. Lett. 2019, 316, 109118,  DOI: 10.1016/j.toxlet.2019.08.024
    194. 194
      Eyles, D. W.; Smith, S.; Kinobe, R.; Hewison, M.; McGrath, J. J. Distribution of the Vitamin D Receptor and 1α-Hydroxylase in Human Brain. J. Chem. Neuroanat. 2005, 29 (1), 2130,  DOI: 10.1016/j.jchemneu.2004.08.006
    195. 195
      Burne, T. H. J.; McGrath, J. J.; Eyles, D. W.; Mackay-Sim, A. Behavioural Characterization of Vitamin D Receptor Knockout Mice. Behav. Brain Res. 2005, 157 (2), 299308,  DOI: 10.1016/j.bbr.2004.07.008
    196. 196
      Beecham, G. W.; Martin, E. R.; Li, Y. J.; Slifer, M. A.; Gilbert, J. R.; Haines, J. L.; Pericak-Vance, M. A. Genome-Wide Association Study Implicates a Chromosome 12 Risk Locus for Late-Onset Alzheimer Disease. Am. J. Hum. Genet. 2009, 84 (1), 3543,  DOI: 10.1016/j.ajhg.2008.12.008
    197. 197
      Butler, M. W.; Burt, A.; Edwards, T. L.; Zuchner, S.; Scott, W. K.; Martin, E. R.; Vance, J. M.; Wang, L. Vitamin D Receptor Gene as a Candidate Gene for Parkinson Disease. Ann. Hum. Genet. 2011, 75 (2), 201210,  DOI: 10.1111/j.1469-1809.2010.00631.x
    198. 198
      Kim, J.-S.; Kim, Y.-I.; Song, C.; Yoon, I.; Park, J.-W.; Choi, Y.-B.; Kim, H.-T.; Lee, K.-S. Association of Vitamin D Receptor Gene Polymorphism and Parkinson’s Disease in Koreans. J. Korean Med. Sci. 2005, 20 (3), 495498,  DOI: 10.3346/jkms.2005.20.3.495
    199. 199
      Niino, M.; Miyazaki, Y. Genetic Polymorphisms Related to Vitamin D and the Therapeutic Potential of Vitamin D in Multiple Sclerosis. Can. J. Physiol. Pharmacol. 2015, 93 (5), 319325,  DOI: 10.1139/cjpp-2014-0374
    200. 200
      Vinh quôc Luong, K.; Thi Hoàng Nguyên, L. Vitamin D and Parkinson’s Disease. J. Neurosci Res. 2012, 90, 22272236,  DOI: 10.1002/jnr.23115
    201. 201
      Banerjee, A.; Khemka, V. K.; Ganguly, A.; Roy, D.; Ganguly, U.; Chakrabarti, S. Vitamin D and Alzheimer’s Disease: Neurocognition to Therapeutics. Int. J. Alzheimer's Dis. 2015, 2015, 192747,  DOI: 10.1155/2015/192747
    202. 202
      Luong, K.; Nguyen, L. Role of Vitamin D in Parkinson’s Disease. ISRN Neurol. 2012, 2012, 134289  DOI: 10.5402/2012/134289
    203. 203
      Munger, K. L.; Levin, L. I.; Hollis, B. W.; Howard, N. S.; Ascherio, A. Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis. J. Am. Med. Assoc. 2006, 296 (23), 28322838,  DOI: 10.1001/jama.296.23.2832
    204. 204
      Moretti, R.; Morelli, M. E.; Caruso, P. Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact. Int. J. Mol. Sci. 2018, 19 (8), 2245,  DOI: 10.3390/ijms19082245
    205. 205
      Salzer, J.; Hallmans, G.; Nyström, M.; Stenlund, H.; Wadell, G.; Sundström, P. Vitamin D as a Protective Factor in Multiple Sclerosis. Neurology 2012, 79 (21), 21402145,  DOI: 10.1212/WNL.0b013e3182752ea8
    206. 206
      Grimm, M. O. W.; Lauer, A. A.; Grösgen, S.; Thiel, A.; Lehmann, J.; Winkler, J.; Janitschke, D.; Herr, C.; Beisswenger, C.; Bals, R.; Grimm, H. S.; Hartmann, T. Profiling of Alzheimer’s Disease Related Genes in Mild to Moderate Vitamin D Hypovitaminosis. J. Nutr. Biochem. 2019, 67, 123137,  DOI: 10.1016/j.jnutbio.2019.01.015
    207. 207
      Uberti, F.; Morsanuto, V.; Bardelli, C.; Molinari, C. Protective Effects of 1α,25-Dihydroxyvitamin D3 on Cultured Neural Cells Exposed to Catalytic Iron. Physiol. Rep. 2016, 4 (11), e12769,  DOI: 10.14814/phy2.12769
    208. 208
      Ibi, M.; Sawada, H.; Nakanishi, M.; Kume, T.; Katsuki, H.; Kaneko, S.; Shimohama, S.; Akaike, A. Protective Effects of 1α,25-(OH)2D3 against the Neurotoxicity of Glutamate and Reactive Oxygen Species in Mesencephalic Culture. Neuropharmacology 2001, 40 (6), 761771,  DOI: 10.1016/S0028-3908(01)00009-0
    209. 209
      Zhang, D.; Li, M.; Dong, Y.; Zhang, X.; Liu, X.; Chen, Z.; Zhu, Y.; Wang, H.; Liu, X.; Zhu, J.; Shen, Y.; Korner, H.; Ying, S.; Fang, S.; Shen, Y. 1α,25-Dihydroxyvitamin D3 up-Regulates IL-34 Expression in SH-SY5Y Neural Cells. Innate Immun. 2017, 23 (7), 584591,  DOI: 10.1177/1753425917725391
    210. 210
      Jiao, K.-P.; Li, S.-M.; Lv, W.-Y.; Jv, M.-L.; He, H.-Y. Vitamin D3 Repressed Astrocyte Activation Following Lipopolysaccharide Stimulation in Vitro and in Neonatal Rats. NeuroReport 2017, 28 (9), 492497,  DOI: 10.1097/WNR.0000000000000782
    211. 211
      Dursun, E.; Gezen-Ak, D.; Yilmazer, S. A Novel Perspective for Alzheimer’s Disease: Vitamin D Receptor Suppression by Amyloid-β and Preventing the Amyloid-β Induced Alterations by Vitamin D in Cortical Neurons. Journal of Alzheimer’s Disease 2011, 23 (2), 207219,  DOI: 10.3233/JAD-2010-101377
    212. 212
      Niino, M. Vitamin D and Its Immunoregulatory Role in Multiple Sclerosis. Drugs Today (Barc) 2010, 46 (4), 279290,  DOI: 10.1358/dot.2010.46.4.1476498
    213. 213
      Kim, H.; Shin, J.-Y.; Lee, Y.-S.; Yun, S. P.; Maeng, H.-J.; Lee, Y. Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson’s Disease via a Vitamin D Receptor-Dependent Pathway. Int. J. Mol. Sci. 2020, 21 (22), 8538,  DOI: 10.3390/ijms21228538
    214. 214
      Maestro, M. A.; Molnár, F.; Carlberg, C. Vitamin D and Its Synthetic Analogs. J. Med. Chem. 2019, 62 (15), 68546875,  DOI: 10.1021/acs.jmedchem.9b00208
    215. 215
      Bishop, J. E.; Collins, E. D.; Okamura, W. H.; Norman, A. W. Profile of Ligand Specificity of the Vitamin D Binding Protein for 1α,25-dihydroxyvitamin D3 and Its Analogs. J. Bone Miner. Res. 1994, 9 (8), 12771288,  DOI: 10.1002/jbmr.5650090818
    216. 216
      Saito, N.; Matsunaga, T.; Saito, H.; Anzai, M.; Takenouchi, K.; Miura, D.; Namekawa, J.; Ishizuka, S.; Kittaka, A. Further Synthetic and Biological Studies on Vitamin D Hormone Antagonists Based on C24-Alkylation and C2α-Functionalization of 25-Dehydro-1α- Hydroxyvitamin D3–26,23-Lactones. J. Med. Chem. 2006, 49 (24), 70637075,  DOI: 10.1021/jm060797q
    217. 217
      Wiberg, K.; Ljunghall, S.; Binderup, L.; Ljunggren, Ö. Studies on Two New Vitamin D Analogs, EB 1089 and KH 1060: Effects on Bone Resorption and Osteoclast Recruitment in Vitro. Bone 1995, 17 (4), 391395,  DOI: 10.1016/S8756-3282(95)00246-4
    218. 218
      Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M. A.; Leid, M.; De Lera, A. R.; Lotan, R.; Mangelsdorf, D. J.; Gronemeyer, H. International Union of Pharmacology. LXIII. Retinoid X Receptors. Pharmacol. Rev. 2006, 58 (4), 760772,  DOI: 10.1124/pr.58.4.7
    219. 219
      de Lera, A. R.; Bourguet, W.; Altucci, L.; Gronemeyer, H. Design of Selective Nuclear Receptor Modulators: RAR and RXR as a Case Study. Nat. Rev. Drug Discovery 2007, 6 (10), 811820,  DOI: 10.1038/nrd2398
    220. 220
      Dominguez, M.; Alvarez, S.; de Lera, A. R. Natural and Structure-Based RXR Ligand Scaffolds and Their Functions. Curr. Top. Med. Chem. 2017, 17 (6), 631662,  DOI: 10.2174/1568026616666160617072521
    221. 221
      Chaikuad, A.; Pollinger, J.; Rühl, M.; Ni, X.; Kilu, W.; Heering, J.; Merk, D. Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms. Int. J. Mol. Sci. 2020, 21 (22), 8457,  DOI: 10.3390/ijms21228457
    222. 222
      Schierle, S.; Merk, D. Therapeutic Modulation of Retinoid X Receptors - SAR and Therapeutic Potential of RXR Ligands and Recent Patents. Expert Opin. Ther. Pat. 2019, 29 (8), 605621,  DOI: 10.1080/13543776.2019.1643322
    223. 223
      Egea, P. F.; Mitschler, A.; Moras, D. Molecular Recognition of Agonist Ligands by RXRs. Mol. Endocrinol. 2002, 16 (5), 987997,  DOI: 10.1210/mend.16.5.0823
    224. 224
      Zetterstrom, R. H.; Lindqvist, E.; De Urquiza, A. M.; Tomac, A.; Eriksson, U.; Perlmann, T.; Olson, L. Role of Retinoids in the CNS : Differential Expression of Retinoid Binding Proteins and Receptors and Evidence for Presence of Retinoic Acid. Eur. J. Neurosci. 1999, 11 (2), 407416,  DOI: 10.1046/j.1460-9568.1999.00444.x
    225. 225
      Ferré, S.; Fredholm, B. B.; Morelli, M.; Popoli, P.; Fuxe, K. Adenosine – Dopamine Receptor – Receptor Interactions as an Integrative Mechanism in the Basal Ganglia. Trends Neurosci. 1997, 20 (10), 482487,  DOI: 10.1016/S0166-2236(97)01096-5
    226. 226
      Moreno, S.; Farioli-Vecchioli, S.; Cerù, M. P. Immunolocalization of Peroxisome Proliferator-Activated Receptors and Retinoid X Receptors in the Adult Rat CNS. Neuroscience 2004, 123 (1), 131145,  DOI: 10.1016/j.neuroscience.2003.08.064
    227. 227
      Huang, J. K.; Jarjour, A. A.; Nait Oumesmar, B.; Kerninon, C.; Williams, A.; Krezel, W.; Kagechika, H.; Bauer, J.; Zhao, C.; Baron-Van Evercooren, A.; Chambon, P.; Ffrench-Constant, C.; Franklin, R. J. M. Retinoid X Receptor Gamma Signaling Accelerates CNS Remyelination. Nat. Neurosci. 2011, 14 (1), 4553,  DOI: 10.1038/nn.2702
    228. 228
      Hanafy, K. A.; Sloane, J. A. Regulation of Remyelination in Multiple Sclerosis. FEBS Lett. 2011, 585 (23), 38213828,  DOI: 10.1016/j.febslet.2011.03.048
    229. 229
      Vaz, B.; de Lera, Á. R. Advances in Drug Design with RXR Modulators. Expert Opin. Drug Discovery 2012, 7 (11), 10031016,  DOI: 10.1517/17460441.2012.722992
    230. 230
      Koster, K. P.; Smith, C.; Valencia-Olvera, A. C.; Thatcher, G. R. J.; Tai, L. M.; LaDu, M. J. Rexinoids as Therapeutics for Alzheimer’s Disease: Role of APOE. Curr. Top. Med. Chem. 2017, 17 (6), 708720,  DOI: 10.2174/1568026616666160617090227
    231. 231
      Corder, E. H.; Saunders, A. M.; Strittmatter, W. J.; Schmechel, D. E.; Gaskell, P. C.; Small, G. W.; Roses, A. D.; Haines, J. L.; Pericak-Vance, M. A. Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer’s Disease in Late Onset Families. Science 1993, 261 (5123), 921923,  DOI: 10.1126/science.8346443
    232. 232
      Cosentino, S.; Scarmeas, N.; Helzner, E.; Glymour, M. M.; Brandt, J.; Albert, M.; Blacker, D.; Stern, Y. APOE Epsilon 4 Allele Predicts Faster Cognitive Decline in Mild Alzheimer Disease. Neurology 2008, 70 (19), 18421849,  DOI: 10.1212/01.wnl.0000304038.37421.cc
    233. 233
      Khachaturian, A. S.; Corcoran, C. D.; Mayer, L. S.; Zandi, P. P.; Breitner, J. C. S. Apolipoprotein E Epsilon4 Count Affects Age at Onset of Alzheimer Disease, but Not Lifetime Susceptibility: The Cache County Study. Arch. Gen. Psychiatry 2004, 61 (5), 518524,  DOI: 10.1001/archpsyc.61.5.518
    234. 234
      Mandrekar-Colucci, S.; Landreth, G. E. Nuclear Receptors as Therapeutic Targets for Alzheimer’s Disease. Expert Opin. Ther. Targets 2011, 15 (9), 10851097,  DOI: 10.1517/14728222.2011.594043
    235. 235
      Koldamova, R.; Fitz, N. F.; Lefterov, I. ATP-Binding Cassette Transporter A1: From Metabolism to Neurodegeneration. Neurobiol. Dis. 2014, 72A, 1321,  DOI: 10.1016/j.nbd.2014.05.007
    236. 236
      Oram, J. F.; Vaughan, A. M. ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease. Circ. Res. 2006, 99 (10), 10311043,  DOI: 10.1161/01.RES.0000250171.54048.5c
    237. 237
      Tai, L. M.; Mehra, S.; Shete, V.; Estus, S.; Rebeck, G. W.; Bu, G.; Ladu, M. J. Soluble ApoE/Aβ Complex: Mechanism and Therapeutic Target for APOE4-Induced AD Risk. Mol. Neurodegener. 2014, 9, 2,  DOI: 10.1186/1750-1326-9-2
    238. 238
      Yu, C.; Youmans, K. L.; Ladu, M. J. Proposed Mechanism for Lipoprotein Remodelling in the Brain. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2010, 1801 (8), 819823,  DOI: 10.1016/j.bbalip.2010.05.001
    239. 239
      Cramer, P. E.; Cirrito, J. R.; Wesson, D. W.; Lee, C. Y. D.; Karlo, J. C.; Zinn, A. E.; Casali, B. T.; Restivo, J. L.; Goebel, W. D.; James, M. J.; Brunden, K. R.; Wilson, D. A.; Landreth, G. E. ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models. Science 2012, 335 (6075), 15031506,  DOI: 10.1126/science.1217697
    240. 240
      Fitz, N. F.; Cronican, A. A.; Lefterov, I.; Koldamova, R. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924c,  DOI: 10.1126/science.1235809
    241. 241
      Price, A. R.; Xu, G.; Siemienski, Z. B.; Smithson, L. A.; Borchelt, D. R.; Golde, T. E.; Felsenstein, K. M. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924d,  DOI: 10.1126/science.1234089
    242. 242
      Tesseur, I.; Lo, A. C.; Roberfroid, A.; Dietvorst, S.; Van Broeck, B.; Borgers, M.; Gijsen, H.; Moechars, D.; Mercken, M.; Kemp, J.; D'Hooge, R.; De Strooper, B. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924-e,  DOI: 10.1126/science.1233937
    243. 243
      Veeraraghavalu, K.; Zhang, C.; Miller, S.; Hefendehl, J. K.; Rajapaksha, T. W.; Ulrich, J.; Jucker, M.; Holtzman, D. M.; Tanzi, R. E.; Vassar, R.; Sisodia, S. S. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models.. Science 2013, 340 (6135), 924f,  DOI: 10.1126/science.1235505
    244. 244
      Ghosal, K.; Haag, M.; Verghese, P. B.; West, T.; Veenstra, T.; Braunstein, J. B.; Bateman, R. J.; Holtzman, D. M.; Landreth, G. E. A Randomized Controlled Study to Evaluate the Effect of Bexarotene on Amyloid-β and Apolipoprotein E Metabolism in Healthy Subjects. Alzheimer’s Dement. Transl. Res. Clin. Interv. 2016, 2 (2), 110120,  DOI: 10.1016/j.trci.2016.06.001
    245. 245
      Cummings, J. L.; Zhong, K.; Kinney, J. W.; Heaney, C.; Moll-Tudla, J.; Joshi, A.; Pontecorvo, M.; Devous, M.; Tang, A.; Bena, J. Double-Blind, Placebo-Controlled, Proof-of-Concept Trial of Bexarotene in Moderate Alzheimer’s Disease. Alzheimer’s Res. Ther. 2016, 8 (4), 4,  DOI: 10.1186/s13195-016-0173-2
    246. 246
      Lammi, J.; Perlmann, T.; Aarnisalo, P. Corepressor Interaction Differentiates the Permissive and Non-Permissive Retinoid X Receptor Heterodimers. Arch. Biochem. Biophys. 2008, 472 (2), 105114,  DOI: 10.1016/j.abb.2008.02.003
    247. 247
      Schrage, K.; Koopmans, G.; Joosten, E. A. J.; Mey, J. Macrophages and Neurons Are Targets of Retinoic Acid Signaling after Spinal Cord Contusion Injury. Eur. J. Neurosci. 2006, 23 (2), 285295,  DOI: 10.1111/j.1460-9568.2005.04534.x
    248. 248
      Natrajan, M. S.; de la Fuente, A. G.; Crawford, A. H.; Linehan, E.; Nuñez, V.; Johnson, K. R.; Wu, T.; Fitzgerald, D. C.; Ricote, M.; Bielekova, B.; Franklin, R. J. M. Retinoid X Receptor Activation Reverses Age-Related Deficiencies in Myelin Debris Phagocytosis and Remyelination. Brain 2015, 138 (12), 35813597,  DOI: 10.1093/brain/awv289
    249. 249
      Baer, A. S.; Syed, Y. A.; Kang, S. U.; Mitteregger, D.; Vig, R.; Ffrench-Constant, C.; Franklin, R. J. M.; Altmann, F.; Lubec, G.; Kotter, M. R. Myelin-Mediated Inhibition of Oligodendrocyte Precursor Differentiation Can Be Overcome by Pharmacological Modulation of Fyn-RhoA and Protein Kinase C Signalling. Brain 2009, 132 (2), 465481,  DOI: 10.1093/brain/awn334
    250. 250
      Kotter, M. R.; Zhao, C.; van Rooijen, N.; Franklin, R. J.M. Macrophage-Depletion Induced Impairment of Experimental CNS Remyelination Is Associated with a Reduced Oligodendrocyte Progenitor Cell Response and Altered Growth Factor Expression. Neurobiol. Dis. 2005, 18 (1), 166175,  DOI: 10.1016/j.nbd.2004.09.019
    251. 251
      Xu, J.; Drew, P. D. 9-Cis-Retinoic Acid Suppresses Inflammatory Responses of Microglia and Astrocytes. J. Neuroimmunol. 2006, 171 (1–2), 135144,  DOI: 10.1016/j.jneuroim.2005.10.004
    252. 252
      Chandraratna, R. A.; Sanders, M. E. WO2017/075607 Treatment of Nervous System Disorders Using Combinations of RXR Agonists and Thyroid Hormones, IO Ther. INC, 2017.
    253. 253
      Volle, D. H. Nuclear Receptors as Pharmacological Targets, Where Are We Now?. Cell. Mol. Life Sci. 2016, 73 (10), 37773780,  DOI: 10.1007/s00018-016-2327-6
    254. 254
      Levin, A. A.; Sturzenbecker, L. J.; Kazmer, S.; Bosakowski, T.; Huselton, C.; Allenby, G.; Speck, J.; Kratzeisen, C.; Rosenberger, M.; Lovey, A.; Grippo, J. F. 9-Cis Retinoic Acid Stereoisomer Binds and Activates the Nuclear Receptor RXR Alpha. Nature 1992, 355 (6358), 359361,  DOI: 10.1038/355359a0
    255. 255
      Goldstein, J. T.; Dobrzyn, A.; Clagett-Dame, M.; Pike, J. W.; Deluca, H. F. Isolation and Characterization of Unsaturated Fatty Acids as Natural Ligands for the Retinoid-X Receptor. Arch. Biochem. Biophys. 2003, 420 (1), 185193,  DOI: 10.1016/j.abb.2003.09.034
    256. 256
      Fitzgerald, P.; Teng, M.; Chandraratna, R. A. S.; Heyman, A.; Allegretto, A. Retinoic Acid Receptor α Expression Correlates with Retinoid-Induced Growth Inhibition of Human Breast Cancer Cells Regardless of Estrogen Receptor Status. Cancer Res. 1997, 57 (13), 26422650
    257. 257
      Vuligonda, V.; Thacher, S. M.; Chandraratna, R. A. Enantioselective Syntheses of Potent Retinoid X Receptor Ligands: Differential Biological Activities of Individual Antipodes. J. Med. Chem. 2001, 44 (14), 22982303,  DOI: 10.1021/jm0100584
    258. 258
      Boehm, M. F.; McClurg, M. R.; Pathirana, C.; Mangelsdorf, D.; White, S. K.; Hebert, J.; Winn, D.; Goldman, M. E.; Heyman, R. A. Synthesis of High Specific Activity [3H]-9-Cis-Retinoic Acid and Its Application for Identifying Retinoids with Unusual Binding Properties. J. Med. Chem. 1994, 37 (3), 408414,  DOI: 10.1021/jm00029a013
    259. 259
      Blair, H. A.; Scott, L. J. Alitretinoin : A Review in Severe Chronic Hand Eczema. Drugs 2016, 76 (13), 12711279,  DOI: 10.1007/s40265-016-0621-0
    260. 260
      Cheer, S. M.; Foster, R. H. Alitretinoin. Am. J. Clin. Dermatol. 2000, 1 (5), 307314,  DOI: 10.2165/00128071-200001050-00005
    261. 261
      Son, J. H.; Park, S. Y.; Cho, Y. S.; Byun, Y. S.; Chung, B. Y.; Cho, H. J.; Kim, H. O.; Park, C. W. Two Cases of Successful Treatment of Refractory Chronic Inflammatory Skin Disease, Atopic Dermatitis and Psoriasis with Oral Alitretinoin. Ann. Dermatol. 2017, 29 (4), 503506,  DOI: 10.5021/ad.2017.29.4.503
    262. 262
      Rühl, R.; Krzyzosiak, A.; Niewiadomska-Cimicka, A.; Rochel, N.; Szeles, L.; Vaz, B.; Wietrzych-Schindler, M.; Álvarez, S.; Szklenar, M.; Nagy, L.; de Lera, A. R.; Krezel, W. 9-Cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice. PLoS Genet. 2015, 11 (6), e1005213,  DOI: 10.1371/journal.pgen.1005213
    263. 263
      de Lera, Á.; Krezel, W.; Rühl, R. An Endogenous Mammalian Retinoid X Receptor Ligand, at Last!. ChemMedChem 2016, 11 (10), 10271037,  DOI: 10.1002/cmdc.201600105
    264. 264
      Neuringer, M.; Anderson, G. J.; Connor, W. E. The Essentiality of N-3 Fatty Acids for the Development and Function of the Retina and Brain. Annu. Rev. Nutr. 1988, 8, 517541,  DOI: 10.1146/annurev.nu.08.070188.002505
    265. 265
      Bourguet, W.; Vivat, V.; Wurtz, J.-M.; Chambon, P.; Gronemeyer, H.; Moras, D. Crystal Structure of a Heterodimeric Complex of RAR and RXR Ligand-Binding Domains. Mol. Cell 2000, 5 (2), 289298,  DOI: 10.1016/S1097-2765(00)80424-4
    266. 266
      Heald, P.; Mehlmauer, M.; Martin, A. G.; Crowley, C. A.; Yocum, R. C.; Reich, S. D. Topical Bexarotene Therapy for Patients with Refractory or Persistent Early-Stage Cutaneous T-Cell Lymphoma: Results of the Phase III Clinical Trial. J. Am. Acad. Dermatol. 2003, 49 (5), 801815,  DOI: 10.1016/S0190-9622(03)01475-0
    267. 267
      Wong, S. F. Oral Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma. Ann. Pharmacother. 2001, 35 (9), 10561065,  DOI: 10.1345/aph.10223
    268. 268
      Boehm, M. F.; Zhang, L.; Badea, B. A.; White, S. K.; Mais, D. E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A. Synthesis and Structure-Activity Relationships of Novel Retinoid X Receptor-Selective Retinoids. J. Med. Chem. 1994, 37 (18), 29302941,  DOI: 10.1021/jm00044a014
    269. 269
      Howell, S. R.; Shirley, M. A.; Grese, T. A.; Neel, D. A.; Wells, K. E.; Ulm, E. H. Bexarotene Metabolism in Rat, Dog, and Human, Synthesis of Oxidative Metabolites, and in Vitro Activity at Retinoid Receptors. Drug Metab. Dispos. 2001, 29 (7), 990998
    270. 270
      Wang, Y.; Rong, J.; Zhang, J.; Liu, Y.; Meng, X.; Guo, H.; Liu, H.; Chen, L. Morphology, in Vivo Distribution and Antitumor Activity of Bexarotene Nanocrystals in Lung Cancer. Drug Dev. Ind. Pharm. 2017, 43 (1), 132141,  DOI: 10.1080/03639045.2016.1225752
    271. 271
      Lowenthal, J.; Hull, S. C.; Pearson, S. D. The Ethics of Early Evidence - Preparing for a Possible Breakthrough in Alzheimer’s Disease. N. Engl. J. Med. 2012, 367 (6), 488490,  DOI: 10.1056/NEJMp1203104
    272. 272
      Takamatsu, K.; Takano, A.; Yakushiji, N.; Morishita, K.; Matsuura, N.; Makishima, M.; Ali, H. I.; Akaho, E.; Tai, A.; Sasaki, K.; Kakuta, H. Reduction of Lipophilicity at the Lipophilic Domain of RXR Agonists Enables Production of Subtype Preference: RXRa- Preferential Agonist Possessing a Sulfonamide Moiety. ChemMedChem 2008, 3 (3), 454460,  DOI: 10.1002/cmdc.200700265
    273. 273
      Boehm, M. F.; Zhang, L.; Zhi, L.; McClurg, M. R.; Berger, E.; Wagoner, M.; Mais, D. E.; Suto, C. M.; Davies, P. J. A.; Heyman, R. A.; Nadzan, A. M. Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells. J. Med. Chem. 1995, 38 (16), 31463155,  DOI: 10.1021/jm00016a018
    274. 274
      Takamatsu, K.; Takano, A.; Yakushiji, N.; Morohashi, K.; Morishita, K.; Matsuura, N.; Makishima, M.; Tai, A.; Sasaki, K.; Kakuta, H. The First Potent Subtype-Selective Retinoid X Receptor (RXR) Agonist Possessing a 3-Isopropoxy-4-isopropylphenylamino Moiety, NEt-3IP (RXRα/B-dual Agonist). ChemMedChem 2008, 3 (5), 780787,  DOI: 10.1002/cmdc.200700313
    275. 275
      Pollinger, J.; Merk, D. Therapeutic Applications of the Versatile Fatty Acid Mimetic WY14643. Expert Opin. Ther. Pat. 2017, 27 (4), 517525,  DOI: 10.1080/13543776.2017.1272578
    276. 276
      Watanabe, M.; Kakuta, H. Retinoid X Receptor Antagonists. Int. J. Mol. Sci. 2018, 19 (8), 2354  DOI: 10.3390/ijms19082354
    277. 277
      Nakayama, M.; Yamada, S.; Ohsawa, F.; Ohta, Y.; Kawata, K.; Makishima, M.; Kakuta, H. Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB. ACS Med. Chem. Lett. 2011, 2 (12), 896900,  DOI: 10.1021/ml200197e
    278. 278
      Merk, D.; Grisoni, F.; Friedrich, L.; Gelzinyte, E.; Schneider, G. Computer-Assisted Discovery of Retinoid X Receptor Modulating Natural Products and Isofunctional Mimetics. J. Med. Chem. 2018, 61 (12), 54425447,  DOI: 10.1021/acs.jmedchem.8b00494
    279. 279
      Merk, D.; Grisoni, F.; Friedrich, L.; Gelzinyte, E.; Schneider, G. Scaffold Hopping from Synthetic RXR Modulators by Virtual Screening and de Novo Design. MedChemComm 2018, 9, 12891292,  DOI: 10.1039/C8MD00134K
    280. 280
      Pollinger, J.; Schierle, S.; Gellrich, L.; Ohrndorf, J.; Kaiser, A.; Heitel, P.; Chaikuad, A.; Knapp, S.; Merk, D. A Novel Biphenyl-Based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences. ACS Med. Chem. Lett. 2019, 10 (9), 13461352,  DOI: 10.1021/acsmedchemlett.9b00306
    281. 281
      Islam, M. M.; Zhang, C.-L. TLX: A Master Regulator for Neural Stem Cell Maintenance and Neurogenesis. Biochim. Biophys. Acta, Gene Regul. Mech. 2015, 1849 (2), 210216,  DOI: 10.1016/j.bbagrm.2014.06.001
    282. 282
      Shi, Y.; Lie, D. C.; Taupin, P.; Nakashima, K.; Ray, J.; Yu, R. T.; Gage, F. H.; Evans, R. M. Expression and Function of Orphan Nuclear Receptor TLX in Adult Neural Stem Cells. Nature 2004, 427 (6969), 7883,  DOI: 10.1038/nature02211
    283. 283
      Miyawaki, T.; Uemura, A.; Dezawa, M.; Yu, R. T.; Ide, C.; Nishikawa, S.; Honda, Y.; Tanabe, Y.; Tanabe, T. Tlx, an Orphan Nuclear Receptor, Regulates Cell Numbers and Astrocyte Development in the Developing Retina. J. Neurosci. 2004, 24 (37), 81248134,  DOI: 10.1523/JNEUROSCI.2235-04.2004
    284. 284
      Monaghan, A. P.; Grau, E.; Bock, D.; Schütz, G. The Mouse Homolog of the Orphan Nuclear Receptor Tailless Is Expressed in the Developing Forebrain. Development 1995, 121 (3), 839853,  DOI: 10.1242/dev.121.3.839
    285. 285
      Li, S.; Sun, G.; Murai, K.; Ye, P.; Shi, Y. Characterization of TLX Expression in Neural Stem Cells and Progenitor Cells in Adult Brains. PLoS One 2012, 7 (8), e43324,  DOI: 10.1371/journal.pone.0043324
    286. 286
      Benod, C.; Villagomez, R.; Webb, P. TLX: An Elusive Receptor. J. Steroid Biochem. Mol. Biol. 2016, 157, 4147,  DOI: 10.1016/j.jsbmb.2015.11.001
    287. 287
      Yokoyama, A.; Takezawa, S.; Schule, R.; Kitagawa, H.; Kato, S. Transrepressive Function of TLX Requires the Histone Demethylase LSD1. Mol. Cell. Biol. 2008, 28 (12), 39954003,  DOI: 10.1128/MCB.02030-07
    288. 288
      Zhang, C.-L.; Zou, Y.; Yu, R. T.; Gage, F. H.; Evans, R. M. Nuclear Receptor TLX Prevents Retinal Dystrophy and Recruits the Corepressor Atrophin1. Genes Dev. 2006, 20 (10), 13081320,  DOI: 10.1101/gad.1413606
    289. 289
      Estruch, S. B.; Buzón, V.; Carbó, L. R.; Schorova, L.; Lüders, J.; Estébanez-Perpiñá, E. The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates Its Transrepressive Function. PLoS One 2012, 7 (6), e37963,  DOI: 10.1371/journal.pone.0037963
    290. 290
      Sun, G.; Yu, R. T.; Evans, R. M.; Shi, Y. Orphan Nuclear Receptor TLX Recruits Histone Deacetylases to Repress Transcription and Regulate Neural Stem Cell Proliferation. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (39), 1528215287,  DOI: 10.1073/pnas.0704089104
    291. 291
      Griffett, K.; Bedia-Diaz, G.; Hegazy, L.; de Vera, I. M. S.; Wanninayake, U. S.; Billon, C.; Koelblen, T.; Wilhelm, M. L.; Burris, T. P. The Orphan Nuclear Receptor TLX Is a Receptor for Synthetic and Natural Retinoids. Cell Chem. Biol. 2020, 27 (10), 12721284,  DOI: 10.1016/j.chembiol.2020.07.013
    292. 292
      Benod, C.; Villagomez, R.; Filgueira, C. S.; Hwang, P. K.; Leonard, P. G.; Poncet-Montange, G.; Rajagopalan, S.; Fletterick, R. J.; Gustafsson, J.-Å.; Webb, P. The Human Orphan Nuclear Receptor Tailless (TLX, NR2E1) Is Druggable. PLoS One 2014, 9 (6), e99440,  DOI: 10.1371/journal.pone.0099440
    293. 293
      Zhi, X.; Zhou, X. E.; He, Y.; Searose-Xu, K.; Zhang, C.-L.; Tsai, C.-C.; Melcher, K.; Xu, H. E. Structural Basis for Corepressor Assembly by the Orphan Nuclear Receptor TLX. Genes Dev. 2015, 29 (4), 440450,  DOI: 10.1101/gad.254904.114
    294. 294
      Tan, M. H. E.; Zhou, X. E.; Soon, F.-F.; Li, X.; Li, J.; Yong, E.-L.; Melcher, K.; Xu, H. E. The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation. PLoS One 2013, 8 (9), e74359,  DOI: 10.1371/journal.pone.0074359
    295. 295
      Sablin, E. P.; Woods, A.; Krylova, I. N.; Hwang, P.; Ingraham, H. A.; Fletterick, R. J. The Structure of Corepressor Dax-1 Bound to Its Target Nuclear Receptor LRH-1. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (47), 1839018395,  DOI: 10.1073/pnas.0808936105
    296. 296
      Kandel, P.; Semerci, F.; Bajic, A.; Baluya, D.; Ma, L.; Chen, K.; Cao, A.; Phongmekhin, T.; Matinyan, N.; Choi, W.; Jiménez-Panizo, A.; Chamakuri, S.; Raji, I. O.; Chang, L.; Fuentes-Prior, P.; MacKenzie, K. R.; Benn, C. L.; Estébanez-Perpiñá, E.; Venken, K.; Moore, D. D.; Young, D. W.; Maletic-Savatic, M. Oleic Acid Triggers Hippocampal Neurogenesis by Binding to TLX/NR2E1. bioRxiv 2020, 2020.10.28.359810.
    297. 297
      Niu, W.; Zou, Y.; Shen, C.; Zhang, C.-L. Activation of Postnatal Neural Stem Cells Requires Nuclear Receptor TLX. J. Neurosci. 2011, 31 (39), 1381613828,  DOI: 10.1523/JNEUROSCI.1038-11.2011
    298. 298
      Roy, K.; Kuznicki, K.; Wu, Q.; Sun, Z.; Bock, D.; Schutz, G.; Vranich, N.; Monaghan, A. P. The Tlx Gene Regulates the Timing of Neurogenesis in the Cortex. J. Neurosci. 2004, 24 (38), 83338345,  DOI: 10.1523/JNEUROSCI.1148-04.2004
    299. 299
      Shi, Y.; Sun, G.; Zhao, C.; Stewart, R. Neural Stem Cell Self-Renewal. Crit. Rev. Oncol. Hematol. 2008, 65 (1), 4353,  DOI: 10.1016/j.critrevonc.2007.06.004
    300. 300
      Elmi, M.; Matsumoto, Y.; Zeng, Z.; Lakshminarasimhan, P.; Yang, W.; Uemura, A.; Nishikawa, S.; Moshiri, A.; Tajima, N.; Agren, H.; Funa, K. TLX Activates MASH1 for Induction of Neuronal Lineage Commitment of Adult Hippocampal Neuroprogenitors. Mol. Cell. Neurosci. 2010, 45 (2), 121131,  DOI: 10.1016/j.mcn.2010.06.003
    301. 301
      Liu, H.-K.; Belz, T.; Bock, D.; Takacs, A.; Wu, H.; Lichter, P.; Chai, M.; Schütz, G. The Nuclear Receptor Tailless Is Required for Neurogenesis in the Adult Subventricular Zone. Genes Dev. 2008, 22 (18), 24732478,  DOI: 10.1101/gad.479308
    302. 302
      Monaghan, A. P.; Bock, D.; Gass, P.; Schwger, A.; Wolfer, D. P.; Lipp, H.-P.; Schütz, G. Defective Limbic System in Mice Lacking the Tailless Gene. Nature 1997, 390 (6659), 515517,  DOI: 10.1038/37364
    303. 303
      Yu, R. T.; Chiang, M.-Y.; Tanabe, T.; Kobayashi, M.; Yasuda, K.; Evans, R. M.; Umesono, K. The Orphan Nuclear Receptor Tlx Regulates Pax2 and Is Essential for Vision. Proc. Natl. Acad. Sci. U. S. A. 2000, 97 (6), 26212625,  DOI: 10.1073/pnas.050566897
    304. 304
      Juárez, P.; Valdovinos, M. G.; May, M. E.; Lloyd, B. P.; Couppis, M. H.; Kennedy, C. H. Serotonin2A/C Receptors Mediate the Aggressive Phenotype of TLX Gene Knockout Mice. Behav. Brain Res. 2013, 256, 354361,  DOI: 10.1016/j.bbr.2013.07.044
    305. 305
      Murai, K.; Qu, Q.; Sun, G.; Ye, P.; Li, W.; Asuelime, G.; Sun, E.; Tsai, G. E.; Shi, Y. Nuclear Receptor TLX Stimulates Hippocampal Neurogenesis and Enhances Learning and Memory in a Transgenic Mouse Model. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (25), 91159120,  DOI: 10.1073/pnas.1406779111
    306. 306
      O’Leary, J. D.; Kozareva, D. A.; Hueston, C. M.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. The Nuclear Receptor Tlx Regulates Motor, Cognitive and Anxiety-Related Behaviours during Adolescence and Adulthood. Behav. Brain Res. 2016, 306, 3647,  DOI: 10.1016/j.bbr.2016.03.022
    307. 307
      Kozareva, D. A.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. Deletion of TLX and Social Isolation Impairs Exercise-Induced Neurogenesis in the Adolescent Hippocampus. Hippocampus 2018, 28 (1), 311,  DOI: 10.1002/hipo.22805
    308. 308
      O’Leary, J. D.; O’Leary, O. F.; Cryan, J. F.; Nolan, Y. M. Regulation of Behaviour by the Nuclear Receptor TLX. Genes, Brain Behav. 2018, 17 (3), e12357,  DOI: 10.1111/gbb.12357
    309. 309
      Kumar, R. A.; McGhee, K. A.; Leach, S.; Bonaguro, R.; Maclean, A.; Aguirre-Hernandez, R.; Abrahams, B. S.; Coccaro, E. F.; Hodgins, S.; Turecki, G.; Condon, A.; Muir, W. J.; Brooks-Wilson, A. R.; Blackwood, D. H.; Simpson, E. M. Initial Association of NR2E1 with Bipolar Disorder and Identification of Candidate Mutations in Bipolar Disorder, Schizophrenia, and Aggression through Resequencing. Am. J. Med. Genet., Part B 2008, 147B (6), 880889,  DOI: 10.1002/ajmg.b.30696
    310. 310
      Wang, Y. Y.; Hsu, S. H.; Tsai, H. Y.; Cheng, M. C. Genetic Analysis of the NR2E1 Gene as a Candidate Gene of Schizophrenia. Psychiatry Res. 2020, 293, 113386,  DOI: 10.1016/j.psychres.2020.113386
    311. 311
      Liu, H. K.; Wang, Y.; Belz, T.; Bock, D.; Takacs, A.; Radlwimmer, B.; Barbus, S.; Reifenberger, G.; Lichter, P.; Schütz, G. The Nuclear Receptor Tailless Induces Long-Term Neural Stem Cell Expansion and Brain Tumor Initiation. Genes Dev. 2010, 24 (7), 683695,  DOI: 10.1101/gad.560310
    312. 312
      Park, H.-J.; Kim, J.-K.; Jeon, H.-M.; Oh, S.-Y.; Kim, S.-H.; Park, M.-J.; Soeda, A.; Nam, D.-H.; Kim, H. The Neural Stem Cell Fate Determinant TLX Promotes Tumorigenesis and Genesis of Cells Resembling Glioma Stem Cells. Mol. Cells 2010, 30 (5), 403408,  DOI: 10.1007/s10059-010-0122-z
    313. 313
      Louis, D. N.; Ohgaki, H.; Wiestler, O. D.; Cavenee, W. K.; Burger, P. C.; Jouvet, A.; Scheithauer, B. W.; Kleihues, P. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica 2007, 114, 97109
    314. 314
      Cui, Q.; Yang, S.; Ye, P.; Tian, E.; Sun, G.; Zhou, J.; Sun, G.; Liu, X.; Chen, C.; Murai, K.; Zhao, C.; Azizian, K. T.; Yang, L.; Warden, C.; Wu, X.; D’Apuzzo, M.; Brown, C.; Badie, B.; Peng, L.; Riggs, A. D.; Rossi, J. J.; Shi, Y. Downregulation of TLX Induces TET3 Expression and Inhibits Glioblastoma Stem Cell Self-Renewal and Tumorigenesis. Nat. Commun. 2016, 7, 10637,  DOI: 10.1038/ncomms10637
    315. 315
      Dueva, E.; Singh, K.; Kalyta, A.; LeBlanc, E.; Rennie, P. S.; Cherkasov, A. Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor. Molecules 2018, 23 (11), 2967,  DOI: 10.3390/molecules23112967
    316. 316
      Milbrandt, J. Nerve Growth Factor Induces a Gene Homologous to the Glucocorticoid Receptor Gene. Neuron 1988, 1 (3), 183188,  DOI: 10.1016/0896-6273(88)90138-9
    317. 317
      Wang, Z.; Benoit, G.; Liu, J.; Prasad, S.; Aarnisalo, P.; Liu, X.; Xu, H.; Walker, N. P. C.; Perlmann, T. Structure and Function of Nurr1 Identifies a Class of Ligand- Independent Nuclear Receptors. Nature 2003, 423 (6939), 555560,  DOI: 10.1038/nature01645
    318. 318
      Murphy, E. P.; Conneely, O. M. Neuroendocrine Regulation of the Hypothalamic Pituitary Adrenal Axis by the Nurr1/Nur77 Subfamily of Nuclear Receptors. Mol. Endocrinol. 1997, 11 (1), 3947,  DOI: 10.1210/mend.11.1.9874
    319. 319
      Paulsen, R. E.; Granås, K.; Johnsen, H.; Rolseth, V.; Sterri, S. Three Related Brain Nuclear Receptors, NGFI-B, Nurr1, and NOR-1, as Transcriptional Activators. J. Mol. Neurosci. 1995, 6 (4), 249255,  DOI: 10.1007/BF02736784
    320. 320
      Maira, M.; Martens, C.; Philips, A.; Drouin, J. Heterodimerization between Members of the Nur Subfamily of Orphan Nuclear Receptors as a Novel Mechanism for Gene Activation. Mol. Cell. Biol. 1999, 19 (11), 75497557,  DOI: 10.1128/MCB.19.11.7549
    321. 321
      Perlmann, T.; Jansson, L. A Novel Pathway for Vitamin A Signaling Mediated by RXR Heterodimerization with NGFI-B and NURR1. Genes Dev. 1995, 9 (7), 769782,  DOI: 10.1101/gad.9.7.769
    322. 322
      Xiao, Q.; Castillo, S. O.; Nikodem, V. M. Distribution of Messenger RNAs for the Orphan Nuclear Receptors NURR1 and NUR77 (NGFI-B) in Adult Rat Brain Using in Situ Hybridization. Neuroscience 1996, 75 (1), 221230,  DOI: 10.1016/0306-4522(96)00159-5
    323. 323
      Zetterström, R. H.; Williams, R.; Perlmann, T.; Olson, L. Cellular Expression of the Immediate Early Transcription Factors Nurr1 and NGFI-B Suggests a Gene Regulatory Role in Several Brain Regions Including the Nigrostriatal Dopamine System. Mol. Brain Res. 1996, 41 (1–2), 111120,  DOI: 10.1016/0169-328X(96)00074-5
    324. 324
      Chao, L. C.; Wroblewski, K.; Zhang, Z.; Pei, L.; Vergnes, L.; Ilkayeva, O. R.; Ding, S. Y.; Reue, K.; Watt, M. J.; Newgard, C. B.; Pilch, P. F.; Hevener, A. L.; Tontonoz, P. Insulin Resistance and Altered Systemic Glucose Metabolism in Mice Lacking Nur77. Diabetes 2009, 58 (12), 27882796,  DOI: 10.2337/db09-0763
    325. 325
      Zhan, Y.; Chen, Y.; Zhang, Q.; Zhuang, J.; Tian, M.; Chen, H.; Zhang, L.; Zhang, H.; He, J.; Wang, W.; Wu, R.; Wang, Y.; Shi, C.; Yang, K.; Li, A.; Xin, Y.; Li, T. Y.; Yang, J. Y.; Zheng, Z.; Yu, C.; Lin, S.-C.; Chang, C.; Huang, P.; Lin, T.; Wu, Q. The Orphan Nuclear Receptor Nur77 Regulates LKB1 Localization and Activates AMPK. Nat. Chem. Biol. 2012, 8 (11), 897904,  DOI: 10.1038/nchembio.1069
    326. 326
      Kurakula, K.; Vos, M.; Logiantara, A.; Roelofs, J. J.; Nieuwenhuis, M. A.; Koppelman, G. H.; Postma, D. S.; van Rijt, L. S.; de Vries, C. J. M. Nuclear Receptor Nur77 Attenuates Airway Inflammation in Mice by Suppressing NF-KB Activity in Lung Epithelial Cells. J. Immunol. 2015, 195 (4), 13881398,  DOI: 10.4049/jimmunol.1401714
    327. 327
      Hamers, A. A.J.; Vos, M.; Rassam, F.; Marinkovic, G.; Kurakula, K.; van Gorp, P. J.; de Winther, M. P.J.; Gijbels, M. J.J.; de Waard, V.; de Vries, C. J.M. Bone Marrow-Specific Deficiency of Nuclear Receptor Nur77 Enhances Atherosclerosis. Circ. Res. 2012, 110 (3), 428438,  DOI: 10.1161/CIRCRESAHA.111.260760
    328. 328
      Hanna, R. N.; Shaked, I.; Hubbeling, H. G.; Punt, J. A.; Wu, R.; Herrley, E.; Zaugg, C.; Pei, H.; Geissmann, F.; Ley, K.; Hedrick, C. C. NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis. Circ. Res. 2012, 110 (3), 416427,  DOI: 10.1161/CIRCRESAHA.111.253377
    329. 329
      De Silva, S.; Han, S.; Zhang, X.; Huston, D. P.; Winoto, A.; Zheng, B. Reduction of the Incidence and Severity of Collagen-Induced Arthritis by Constitutive Nur77 Expression in the T Cell Lineage. Arthritis Rheum. 2005, 52 (1), 333338,  DOI: 10.1002/art.20736
    330. 330
      Li, L.; Liu, Y.; Chen, H.; Li, F.; Wu, J.; Zhang, H.; He, J.; Xing, Y.; Chen, Y.; Wang, W.; Tian, X.; Li, A.; Zhang, Q.; Huang, P.; Han, J.; Lin, T.; Wu, Q. Impeding the Interaction between Nur77 and P38 Reduces LPS-Induced Inflammation. Nat. Chem. Biol. 2015, 11 (5), 339346,  DOI: 10.1038/nchembio.1788
    331. 331
      Beard, J. A.; Tenga, A.; Chen, T. The Interplay of NR4A Receptors and the Oncogene-Tumor Suppressor Networks in Cancer. Cell. Signalling 2015, 27 (2), 257266,  DOI: 10.1016/j.cellsig.2014.11.009
    332. 332
      Li, H.; Kolluri, S. K.; Gu, J.; Dawson, M. I.; Cao, X.; Hobbs, P. D.; Lin, B.; Chen, G.; Lu, J.; Lin, F.; Xie, Z.; Fontana, J. A.; Reed, J. C.; Zhang, X. Cytochrome c Release and Apoptosis Induced by Mitochondrial Targeting of Nuclear Orphan Receptor TR3. Science 2000, 289 (5482), 11591164,  DOI: 10.1126/science.289.5482.1159
    333. 333
      Cao, X.; Liu, W.; Lin, F.; Li, H.; Kolluri, S. K.; Lin, B.; Han, Y.; Dawson, M. I.; Zhang, X. Retinoid X Receptor Regulates Nur77/Thyroid Hormone Receptor 3-Dependent Apoptosis by Modulating Its Nuclear Export and Mitochondrial Targeting. Mol. Cell. Biol. 2004, 24 (22), 97059725,  DOI: 10.1128/MCB.24.22.9705-9725.2004
    334. 334
      Gilbert, F.; Morissette, M.; St-Hilaire, M.; Paquet, B.; Rouillard, C.; Di Paolo, T.; Lévesque, D. Nur77 Gene Knockout Alters Dopamine Neuron Biochemical Activity and Dopamine Turnover. Biol. Psychiatry 2006, 60 (6), 538547,  DOI: 10.1016/j.biopsych.2006.04.023
    335. 335
      Rouillard, C.; Baillargeon, J.; Paquet, B.; St-Hilaire, M.; Maheux, J.; Lévesque, C.; Darlix, N.; Majeur, S.; Lévesque, D. Genetic Disruption of the Nuclear Receptor Nur77 (Nr4a1) in Rat Reduces Dopamine Cell Loss and L-Dopa-Induced Dyskinesia in Experimental Parkinson’s Disease. Exp. Neurol. 2018, 304, 143153,  DOI: 10.1016/j.expneurol.2018.03.008
    336. 336
      Novak, G.; Gallo, A.; Zai, C. C.; Meltzer, H. Y.; Lieberman, J. A.; Potkin, S. G.; Voineskos, A. N.; Remington, G.; Kennedy, J. L.; Levesque, D.; Le Foll, B. Association of the Orphan Nuclear Receptor NR4A1 with Tardive Dyskinesia. Psychiatr. Genet. 2010, 20 (1), 3943,  DOI: 10.1097/YPG.0b013e3283351221
    337. 337
      St-Hilaire, M.; Bourhis, E.; Lévesque, D.; Rouillard, C. Impaired Behavioural and Molecular Adaptations to Dopamine Denervation and Repeated L-DOPA Treatment in Nur77-Knockout Mice. Eur. J. Neurosci. 2006, 24 (3), 795805,  DOI: 10.1111/j.1460-9568.2006.04954.x
    338. 338
      Éthier, I.; Beaudry, G.; St-Hilaire, M.; Milbrandt, J.; Rouillard, C.; Lévesque, D. The Transcription Factor NGFI-B (Nur77) and Retinoids Play a Critical Role in Acute Neuroleptic-Induced Extrapyramidal Effect and Striatal Neuropeptide Gene Expression. Neuropsychopharmacology 2004, 29 (2), 335346,  DOI: 10.1038/sj.npp.1300318
    339. 339
      Mahmoudi, S.; Samadi, P.; Gilbert, F.; Ouattara, B.; Morissette, M.; Grégoire, L.; Rouillard, C.; Di Paolo, T.; Lévesque, D. Nur77 MRNA Levels and L-Dopa-Induced Dyskinesias in MPTP Monkeys Treated with Docosahexaenoic Acid. Neurobiol. Dis. 2009, 36 (1), 213222,  DOI: 10.1016/j.nbd.2009.07.017
    340. 340
      Mount, M. P.; Zhang, Y.; Amini, M.; Callaghan, S.; Kulczycki, J.; Mao, Z.; Slack, R. S.; Anisman, H.; Park, D. S. Perturbation of Transcription Factor Nur77 Expression Mediated by Myocyte Enhancer Factor 2D (MEF2D) Regulates Dopaminergic Neuron Loss in Response to 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP). J. Biol. Chem. 2013, 288 (20), 1436214371,  DOI: 10.1074/jbc.M112.439216
    341. 341
      Éthier, I.; Kagechika, H.; Shudo, K.; Rouillard, C.; Lévesque, D. Docosahexaenoic Acid Reduces Haloperidol-Induced Dyskinesias in Mice: Involvement of Nur77 and Retinoid Receptors. Biol. Psychiatry 2004, 56 (7), 522526,  DOI: 10.1016/j.biopsych.2004.06.036
    342. 342
      Wei, X.; Gao, H.; Zou, J.; Liu, X.; Chen, D.; Liao, J.; Xu, Y.; Ma, L.; Tang, B.; Zhang, Z.; Cai, X.; Jin, K.; Xia, Y.; Wang, Q. Contra-Directional Coupling of Nur77 and Nurr1 in Neurodegeneration: A Novel Mechanism for Memantine-Induced Anti-Inflammation and Anti-Mitochondrial Impairment. Mol. Neurobiol. 2016, 53 (9), 58765892,  DOI: 10.1007/s12035-015-9477-7
    343. 343
      Popichak, K. A.; Hammond, S. L.; Moreno, J. A.; Afzali, M. F.; Backos, D. S.; Slayden, R. D.; Safe, S.; Tjalkens, R. B. Compensatory Expression of NuR77 and NURR1 Regulates NF-KB–Dependent Inflammatory Signaling in Astrocytes. Mol. Pharmacol. 2018, 94 (4), 11741186,  DOI: 10.1124/mol.118.112631
    344. 344
      Liu, T.-Y.; Yang, X.-Y.; Zheng, L.-T.; Wang, G.-H.; Zhen, X.-C. Activation of Nur77 in Microglia Attenuates Proinflammatory Mediators Production and Protects Dopaminergic Neurons from Inflammation-Induced Cell Death. J. Neurochem. 2017, 140 (4), 589604,  DOI: 10.1111/jnc.13907
    345. 345
      Yan, J.; Huang, J.; Wu, J.; Fan, H.; Liu, A.; Qiao, L.; Shen, M.; Lai, X. Nur77 Attenuates Inflammatory Responses and Oxidative Stress by Inhibiting Phosphorylated IκB-α in Parkinson’s Disease Cell Model. Aging 2020, 12 (9), 81078119,  DOI: 10.18632/aging.103128
    346. 346
      Liebmann, M.; Hucke, S.; Koch, K.; Eschborn, M.; Ghelman, J.; Chasan, A. I.; Glander, S.; Schädlich, M.; Kuhlencord, M.; Daber, N. M.; Eveslage, M.; Beyer, M.; Dietrich, M.; Albrecht, P.; Stoll, M.; Busch, K. B.; Wiendl, H.; Roth, J.; Kuhlmann, T.; Klotz, L. Nur77 Serves as a Molecular Brake of the Metabolic Switch during T Cell Activation to Restrict Autoimmunity. Proc. Natl. Acad. Sci. U. S. A. 2018, 115 (34), E8017E8026,  DOI: 10.1073/pnas.1721049115
    347. 347
      Rothe, T.; Ipseiz, N.; Faas, M.; Lang, S.; Perez-Branguli, F.; Metzger, D.; Ichinose, H.; Winner, B.; Schett, G.; Krönke, G. The Nuclear Receptor Nr4a1 Acts as a Microglia Rheostat and Serves as a Therapeutic Target in Autoimmune-Driven Central Nervous System Inflammation. J. Immunol. 2017, 198 (10), 38783885,  DOI: 10.4049/jimmunol.1600638
    348. 348
      Zhao, Y.; Liu, Y.; Zheng, D. Alpha 1-Antichymotrypsin/SerpinA3 Is a Novel Target of Orphan Nuclear Receptor Nur77. FEBS J. 2008, 275 (5), 10251038,  DOI: 10.1111/j.1742-4658.2008.06269.x
    349. 349
      Wang, L.; Zheng, Y.; Gao, X.; Liu, Y.; You, X. Retinoid X Receptor Ligand Regulates RXRα/Nur77-Dependent Apoptosis via Modulating Its Nuclear Export and Mitochondrial Targeting. Int. J. Clin. Exp. Pathol. 2017, 10 (11), 1077010780
    350. 350
      Zhan, Y.; Du, X.; Chen, H.; Liu, J.; Zhao, B.; Huang, D.; Li, G.; Xu, Q.; Zhang, M.; Weimer, B. C.; Chen, D.; Cheng, Z.; Zhang, L.; Li, Q.; Li, S.; Zheng, Z.; Song, S.; Huang, Y.; Ye, Z.; Su, W.; Lin, S.-C.; Shen, Y.; Wu, Q. Cytosporone B Is an Agonist for Nuclear Orphan Receptor Nur77. Nat. Chem. Biol. 2008, 4 (9), 548556,  DOI: 10.1038/nchembio.106
    351. 351
      Munoz-Tello, P.; Lin, H.; Khan, P.; De Vera, I. M. S.; Kamenecka, T. M.; Kojetin, D. J. Assessment of NR4A Ligands That Directly Bind and Modulate the Orphan Nuclear Receptor Nurr1. J. Med. Chem. 2020, 63 (24), 1563915654,  DOI: 10.1021/acs.jmedchem.0c00894
    352. 352
      Liu, J.-J.; Zeng, H.-N.; Zhang, L.-R.; Zhan, Y.-Y.; Chen, Y.; Wang, Y.; Wang, J.; Xiang, S.-H.; Liu, W.-J.; Wang, W.-J.; Chen, H.-Z.; Shen, Y.-M.; Su, W.-J.; Huang, P.-Q.; Zhang, H.-K.; Wu, Q. A Unique Pharmacophore for Activation of the Nuclear Orphan Receptor Nur77 In Vivo and In Vitro. Cancer Res. 2010, 70 (9), 36283637,  DOI: 10.1158/0008-5472.CAN-09-3160
    353. 353
      Yang, P.-B.; Hou, P.-P.; Liu, F.-Y.; Hong, W.-B.; Chen, H.-Z.; Sun, X.-Y.; Li, P.; Zhang, Y.; Ju, C.-Y.; Luo, L.-J.; Wu, S.-F.; Zhou, J.-X.; Wang, Z.-J.; He, J.-P.; Li, L.; Zhao, T.-J.; Deng, X.; Lin, T.; Wu, Q. Blocking PPARγ Interaction Facilitates Nur77 Interdiction of Fatty Acid Uptake and Suppresses Breast Cancer Progression. Proc. Natl. Acad. Sci. U. S. A. 2020, 117 (44), 2741227422,  DOI: 10.1073/pnas.2002997117
    354. 354
      Wang, W.; Wang, Y.; Chen, H.; Xing, Y.; Li, F.; Zhang, Q.; Zhou, B.; Zhang, H.; Zhang, J.; Bian, X.; Li, L.; Liu, Y.; Zhao, B.; Chen, Y.; Wu, R.; Li, A.; Yao, L.; Chen, P.; Zhang, Y.; Tian, X.; Beermann, F.; Wu, M.; Han, J.; Huang, P.; Lin, T.; Wu, Q. Orphan Nuclear Receptor TR3 Acts in Autophagic Cell Death via Mitochondrial Signaling Pathway. Nat. Chem. Biol. 2014, 10 (2), 133140,  DOI: 10.1038/nchembio.1406
    355. 355
      Wang, W.; Wang, Y.; Hou, P.-P.; Li, F.-W.; Zhou, B.; Chen, H.-Z.; Bian, X.-L.; Cai, Q.-X.; Xing, Y.-Z.; He, J.-P.; Zhang, H.; Huang, P.-Q.; Lin, T.; Wu, Q. Induction of Autophagic Death in Cancer Cells by Agonizing TR3 and Attenuating Akt2 Activity. Chem. Biol. 2015, 22 (8), 10401051,  DOI: 10.1016/j.chembiol.2015.06.023
    356. 356
      Hu, M.; Luo, Q.; Alitongbieke, G.; Chong, S.; Xu, C.; Xie, L.; Chen, X.; Zhang, D.; Zhou, Y.; Wang, Z.; Ye, X.; Cai, L.; Zhang, F.; Chen, H.; Jiang, F.; Fang, H.; Yang, S.; Liu, J.; Diaz-Meco, M. T.; Su, Y.; Zhou, H.; Moscat, J.; Lin, X.; Zhang, X.-K. Celastrol-Induced Nur77 Interaction with TRAF2 Alleviates Inflammation by Promoting Mitochondrial Ubiquitination and Autophagy. Mol. Cell 2017, 66 (1), 141153,  DOI: 10.1016/j.molcel.2017.03.008
    357. 357
      Jung, Y.-S.; Lee, H.-S.; Cho, H.-R.; Kim, K.-J.; Kim, J.-H.; Safe, S.; Lee, S.-O. Dual Targeting of Nur77 and AMPKα by Isoalantolactone Inhibits Adipogenesis in Vitro and Decreases Body Fat Mass in Vivo. Int. J. Obes. 2019, 43 (5), 952962,  DOI: 10.1038/s41366-018-0276-x
    358. 358
      Vinayavekhin, N.; Saghatelian, A. Discovery of a Protein-Metabolite Interaction between Unsaturated Fatty Acids and the Nuclear Receptor Nur77 Using a Metabolomics Approach. J. Am. Chem. Soc. 2011, 133 (43), 1716817171,  DOI: 10.1021/ja208199h
    359. 359
      Lakshmi, S. P.; Reddy, A. T.; Banno, A.; Reddy, R. C. Molecular, Chemical, and Structural Characterization of Prostaglandin A2 as a Novel Agonist for Nur77. Biochem. J. 2019, 476 (19), 27572767,  DOI: 10.1042/BCJ20190253
    360. 360
      Willems, S.; Kilu, W.; Ni, X.; Chaikuad, A.; Knapp, S.; Heering, J.; Merk, D. The Orphan Nuclear Receptor Nurr1 Is Responsive to Non-Steroidal Anti-Inflammatory Drugs. Commun. Chem. 2020, 3 (1), 85,  DOI: 10.1038/s42004-020-0331-0
    361. 361
      Ordentlich, P.; Yan, Y.; Zhou, S.; Heyman, R. A. Identification of the Antineoplastic Agent 6-Mercaptopurine as an Activator of the Orphan Nuclear Hormone Receptor Nurr1. J. Biol. Chem. 2003, 278 (27), 2479124799,  DOI: 10.1074/jbc.M302167200
    362. 362
      Wansa, K. D. S. A.; Harris, J. M.; Yan, G.; Ordentlich, P.; Muscat, G. E. O. The AF-1 Domain of the Orphan Nuclear Receptor NOR-1 Mediates Trans-Activation, Coactivator Recruitment, and Activation by the Purine Anti-Metabolite 6-Mercaptopurine. J. Biol. Chem. 2003, 278 (27), 2477624790,  DOI: 10.1074/jbc.M300088200
    363. 363
      Yoo, Y. G.; Na, T. Y.; Yang, W. K.; Kim, H. J.; Lee, I. K.; Kong, G.; Chung, J. H.; Lee, M. O. 6-Mercaptopurine, an Activator of Nur77, Enhances Transcriptional Activity of HIF-1α Resulting in New Vessel Formation. Oncogene 2007, 26 (26), 38233834,  DOI: 10.1038/sj.onc.1210149
    364. 364
      Lee, H.-S.; Safe, S.; Lee, S.-O. Inactivation of the Orphan Nuclear Receptor NR4A1 Contributes to Apoptosis Induction by Fangchinoline in Pancreatic Cancer Cells. Toxicol. Appl. Pharmacol. 2017, 332, 3239,  DOI: 10.1016/j.taap.2017.07.017
    365. 365
      Lee, S.-O.; Li, X.; Hedrick, E.; Jin, U.-H.; Tjalkens, R. B.; Backos, D. S.; Li, L.; Zhang, Y.; Wu, Q.; Safe, S. Diindolylmethane Analogs Bind NR4A1 and Are NR4A1 Antagonists in Colon Cancer Cells. Mol. Endocrinol. 2014, 28 (10), 17291739,  DOI: 10.1210/me.2014-1102
    366. 366
      Lee, S. O.; Abdelrahim, M.; Yoon, K.; Chintharlapalli, S.; Papineni, S.; Kim, K.; Wang, H.; Safe, S. Inactivation of the Orphan Nuclear Receptor TR3/Nur77 Inhibits Pancreatic Cancer Cell and Tumor Growth. Cancer Res. 2010, 70 (17), 68246836,  DOI: 10.1158/0008-5472.CAN-10-1992
    367. 367
      Yoon, K.; Lee, S.-O.; Cho, S.-D.; Kim, K.; Khan, S.; Safe, S. Activation of Nuclear TR3 (NR4A1) by a Diindolylmethane Analog Induces Apoptosis and Proapoptotic Genes in Pancreatic Cancer Cells and Tumors. Carcinogenesis 2011, 32 (6), 836842,  DOI: 10.1093/carcin/bgr040
    368. 368
      Liu, J.; Wang, G.-H.; Duan, Y.-H.; Dai, Y.; Bao, Y.; Hu, M.; Zhou, Y.-Q.; Li, M.; Jiang, F.; Zhou, H.; Yao, X.-S.; Zhang, X.-K. Modulation of the Nur77-Bcl-2 Apoptotic Pathway by P38α MAPK. Oncotarget 2017, 8 (41), 6973169745,  DOI: 10.18632/oncotarget.19227
    369. 369
      Yao, L.-M.; He, J.-P.; Chen, H.-Z.; Wang, Y.; Wang, W.-J.; Wu, R.; Yu, C.-D.; Wu, Q. Orphan Receptor TR3 Participates in Cisplatin-Induced Apoptosis via Chk2 Phosphorylation to Repress Intestinal Tumorigenesis. Carcinogenesis 2012, 33 (2), 301311,  DOI: 10.1093/carcin/bgr287
    370. 370
      Qi, H.; Jiang, Z.; Wang, C.; Yang, Y.; Li, L.; He, H.; Yu, Z. Sensitization of Tamoxifen-Resistant Breast Cancer Cells by Z-Ligustilide through Inhibiting Autophagy and Accumulating DNA Damages. Oncotarget 2017, 8 (17), 2930029317,  DOI: 10.18632/oncotarget.16832
    371. 371
      Codina, A.; Benoit, G.; Gooch, J. T.; Neuhaus, D.; Perlmann, T.; Schwabe, J. W. R. Identification of a Novel Co-Regulator Interaction Surface on the Ligand Binding Domain of Nurr1 Using NMR Footprinting. J. Biol. Chem. 2004, 279 (51), 5333853345,  DOI: 10.1074/jbc.M409096200
    372. 372
      Volakakis, N.; Malewicz, M.; Kadkhodai, B.; Perlmann, T.; Benoit, G. Characterization of the Nurr1 Ligand-Binding Domin Co-Activator Interaction Surface. J. Mol. Endocrinol. 2006, 37 (2), 317326,  DOI: 10.1677/jme.1.02106
    373. 373
      Galleguillos, D.; Vecchiola, A.; Fuentealba, J. A.; Ojeda, V.; Alvarez, K.; Gómez, A.; Andrés, M. E. PIASγ Represses the Transcriptional Activation Induced by the Nuclear Receptor Nurr1. J. Biol. Chem. 2004, 279 (3), 20052011,  DOI: 10.1074/jbc.M308113200
    374. 374
      Zetterström, R. H.; Solomin, L.; Jansson, L.; Hoffer, B. J.; Olson, L.; Perlmann, T. Dopamine Neuron Agenesis in Nurr1-Deficient Mice. Science 1997, 276 (5310), 248250,  DOI: 10.1126/science.276.5310.248
    375. 375
      Wallén, Å.; Zetterström, R. H.; Solomin, L.; Arvidsson, M.; Olson, L.; Perlmann, T. Fate of Mesencephalic AHD2-Expressing Dopamine Progenitor Cells in Nurr1Mutant Mice. Exp. Cell Res. 1999, 253 (2), 737746,  DOI: 10.1006/excr.1999.4691
    376. 376
      Smits, S. M.; Ponnio, T.; Conneely, O. M.; Burbach, J. P. H.; Smidt, M. P. Involvement of Nurr1 in Specifying the Neurotransmitter Identity of Ventral Midbrain Dopaminergic Neurons. Eur. J. Neurosci. 2003, 18 (7), 17311738,  DOI: 10.1046/j.1460-9568.2003.02885.x
    377. 377
      Hermanson, E.; Joseph, B.; Castro, D.; Lindqvist, E.; Aarnisalo, P.; Wallén, Å.; Benoit, G.; Hengerer, B.; Olson, L.; Perlmann, T. Nurr1 Regulates Dopamine Synthesis and Storage in MN9D Dopamine Cells. Exp. Cell Res. 2003, 288 (2), 324334,  DOI: 10.1016/S0014-4827(03)00216-7
    378. 378
      Jacobs, F. M. J.; van der Linden, A. J. A.; Wang, Y.; von Oerthel, L.; Sul, H. S.; Burbach, J. P. H.; Smidt, M. P. Identification of Dlk1, Ptpru and Klhl1 as Novel Nurr1 Target Genes in Meso-Diencephalic Dopamine Neurons. Development 2009, 136 (14), 23632373,  DOI: 10.1242/dev.037556
    379. 379
      Gil, M.; McKinney, C.; Lee, M. K.; Eells, J. B.; Phyillaier, M. A.; Nikodem, V. M. Regulation of GTP Cyclohydrolase I Expression by Orphan Receptor Nurr1 in Cell Culture and in Vivo. J. Neurochem. 2007, 101 (1), 142150,  DOI: 10.1111/j.1471-4159.2006.04356.x
    380. 380
      Luo, Y.; Henricksen, L. A.; Giuliano, R. E.; Prifti, L.; Callahan, L. M.; Federoff, H. J. VIP Is a Transcriptional Target of Nurr1 in Dopaminergic Cells. Exp. Neurol. 2007, 203 (1), 221232,  DOI: 10.1016/j.expneurol.2006.08.005
    381. 381
      Wallén, Å.; Castro, D. S.; Zetterström, R. H.; Karlén, M.; Olson, L.; Ericson, J.; Perlmann, T. Orphan Nuclear Receptor Nurr1 Is Essential for Ret Expression in Midbrain Dopamine Neurons and in the Brain Stem. Mol. Cell. Neurosci. 2001, 18 (6), 649663,  DOI: 10.1006/mcne.2001.1057
    382. 382
      Heng, X.; Jin, G.; Zhang, X.; Yang, D.; Zhu, M.; Fu, S.; Li, X.; Le, W. Nurr1 Regulates Top IIβ and Functions in Axon Genesis of Mesencephalic Dopaminergic Neurons. Mol. Neurodegener. 2012, 7 (1), 4,  DOI: 10.1186/1750-1326-7-4
    383. 383
      Montarolo, F.; Martire, S.; Perga, S.; Spadaro, M.; Brescia, I.; Allegra, S.; De Francia, S.; Bertolotto, A. NURR1 Deficiency Is Associated to ADHD-like Phenotypes in Mice. Transl. Psychiatry 2019, 9 (1), 207,  DOI: 10.1038/s41398-019-0544-0
    384. 384
      McCoy, J. M.; Walkenhorst, D. E.; McCauley, K. S.; Elaasar, H.; Everett, J. R.; Mix, K. S. Orphan Nuclear Receptor NR4A2 Induces Transcription of the Immunomodulatory Peptide Hormone Prolactin. J. Inflammation 2015, 12, 13,  DOI: 10.1186/s12950-015-0059-2
    385. 385
      Safe, S.; Jin, U. H.; Morpurgo, B.; Abudayyeh, A.; Singh, M.; Tjalkens, R. B. Nuclear Receptor 4A (NR4A) Family - Orphans No More. J. Steroid Biochem. Mol. Biol. 2016, 157, 4860,  DOI: 10.1016/j.jsbmb.2015.04.016
    386. 386
      Decressac, M.; Volakakis, N.; Björklund, A.; Perlmann, T. NURR1 in Parkinson Disease - From Pathogenesis to Therapeutic Potential. Nat. Rev. Neurol. 2013, 9 (11), 629636,  DOI: 10.1038/nrneurol.2013.209
    387. 387
      Liu, H.; Liu, H.; Li, T.; Cui, J.; Fu, Y.; Ren, J.; Sun, X.; Jiang, P.; Yu, S.; Li, C. NR4A2 Genetic Variation and Parkinson’s Disease: Evidence from a Systematic Review and Meta-Analysis. Neurosci. Lett. 2017, 650, 2532,  DOI: 10.1016/j.neulet.2017.01.062
    388. 388
      Chu, Y.; Le, W.; Kompoliti, K.; Jankovic, J.; Mufson, E. J.; Kordower, J. H. Nurr1 in Parkinson’s Disease and Related Disorders. J. Comp. Neurol. 2006, 494 (3), 495514,  DOI: 10.1002/cne.20828
    389. 389
      Decressac, M.; Kadkhodaei, B.; Mattsson, B.; Laguna, A.; Perlmann, T.; Björklund, A. α-Synuclein-Induced down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons. Sci. Transl. Med. 2012, 4 (163), 163ra156,  DOI: 10.1126/scitranslmed.3004676
    390. 390
      Liu, W.; Gao, Y.; Chang, N. Nurr1 Overexpression Exerts Neuroprotective and Anti-Inflammatory Roles via down-Regulating CCL2 Expression in Both in Vivo and in Vitro Parkinson’s Disease Models. Biochem. Biophys. Res. Commun. 2017, 482 (4), 13121319,  DOI: 10.1016/j.bbrc.2016.12.034
    391. 391
      Volakakis, N.; Tiklova, K.; Decressac, M.; Papathanou, M.; Mattsson, B.; Gillberg, L.; Nobre, A.; Björklund, A.; Perlmann, T. Nurr1 and Retinoid X Receptor Ligands Stimulate Ret Signaling in Dopamine Neurons and Can Alleviate α-Synuclein Disrupted Gene Expression. J. Neurosci. 2015, 35 (42), 1437014385,  DOI: 10.1523/JNEUROSCI.1155-15.2015
    392. 392
      Volakakis, N.; Kadkhodaei, B.; Joodmardi, E.; Wallis, K.; Panman, L.; Silvaggi, J.; Spiegelman, B. M.; Perlmann, T. NR4A Orphan Nuclear Receptors as Mediators of CREB-Dependent Neuroprotection. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (27), 1231712322,  DOI: 10.1073/pnas.1007088107
    393. 393
      Wang, X.; Zhuang, W.; Fu, W.; Wang, X.; Lv, E.; Li, F.; Zhou, S.; Rausch, W.-D.; Wang, X. The Lentiviral-Mediated Nurr1 Genetic Engineering Mesenchymal Stem Cells Protect Dopaminergic Neurons in a Rat Model of Parkinson’s Disease. Am. J. Transl. Res. 2018, 10 (6), 15831599
    394. 394
      Saijo, K.; Winner, B.; Carson, C. T.; Collier, J. G.; Boyer, L.; Rosenfeld, M. G.; Gage, F. H.; Glass, C. K. A Nurr1/CoREST Pathway in Microglia and Astrocytes Protects Dopaminergic Neurons from Inflammation-Induced Death. Cell 2009, 137 (1), 4759,  DOI: 10.1016/j.cell.2009.01.038
    395. 395
      Yi, S.-H.; He, X.-B.; Rhee, Y.-H.; Park, C.-H.; Takizawa, T.; Nakashima, K.; Lee, S.-H. Foxa2 Acts as a Co-Activator Potentiating Expression of the Nurr1-Induced DA Phenotype via Epigenetic Regulation. Development 2014, 141 (4), 761772,  DOI: 10.1242/dev.095802
    396. 396
      Kim, C.-H.; Han, B.-S.; Moon, J.; Kim, D.-J.; Shin, J.; Rajan, S.; Nguyen, Q. T.; Sohn, M.; Kim, W.-G.; Han, M.; Jeong, I.; Kim, K.-S.; Lee, E.-H.; Tu, Y.; Naffin-Olivos, J. L.; Park, C.-H.; Ringe, D.; Yoon, H. S.; Petsko, G. A.; Kim, K.-S. Nuclear Receptor Nurr1 Agonists Enhance Its Dual Functions and Improve Behavioral Deficits in an Animal Model of Parkinson’s Disease. Proc. Natl. Acad. Sci. U. S. A. 2015, 112 (28), 87568761,  DOI: 10.1073/pnas.1509742112
    397. 397
      Rajan, S.; Jang, Y.; Kim, C.-H.; Kim, W.; Toh, H. T.; Jeon, J.; Song, B.; Serra, A.; Lescar, J.; Yoo, J. Y.; Beldar, S.; Ye, H.; Kang, C.; Liu, X.-W.; Feitosa, M.; Kim, Y.; Hwang, D.; Goh, G.; Lim, K.-L.; Park, H. M.; Lee, C. H.; Oh, S. F.; Petsko, G. A.; Yoon, H. S.; Kim, K.-S. PGE1 and PGA1 Bind to Nurr1 and Activate Its Transcriptional Function. Nat. Chem. Biol. 2020, 16, 876886,  DOI: 10.1038/s41589-020-0553-6
    398. 398
      Bruning, J. M.; Wang, Y.; Oltrabella, F.; Tian, B.; Kholodar, S. A.; Liu, H.; Bhattacharya, P.; Guo, S.; Holton, J. M.; Fletterick, R. J.; Jacobson, M. P.; England, P. M. Covalent Modification and Regulation of the Nuclear Receptor Nurr1 by a Dopamine Metabolite. Cell Chem. Biol. 2019, 26 (5), 674685,  DOI: 10.1016/j.chembiol.2019.02.002
    399. 399
      Smith, G. A.; Rocha, E. M.; Rooney, T.; Barneoud, P.; McLean, J. R.; Beagan, J.; Osborn, T.; Coimbra, M.; Luo, Y.; Hallett, P. J.; Isacson, O. A Nurr1 Agonist Causes Neuroprotection in a Parkinson’s Disease Lesion Model Primed with the Toll-Like Receptor 3 DsRNA Inflammatory Stimulant Poly(I:C). PLoS One 2015, 10 (3), e0121072,  DOI: 10.1371/journal.pone.0121072
    400. 400
      Zhang, Z.; Li, X.; Xie, W.; Tuo, H.; Hintermann, S.; Jankovic, J.; Le, W. Anti-Parkinsonian Effects of Nurr1 Activator in Ubiquitin-Proteasome System Impairment Induced Animal Model of Parkinson’s Disease. CNS Neurol. Disord.: Drug Targets 2012, 11 (6), 768773,  DOI: 10.2174/187152712803581155
    401. 401
      Friling, S.; Bergsland, M.; Kjellander, S. Activation of Retinoid X Receptor Increases Dopamine Cell Survival in Models for Parkinson’s Disease. BMC Neurosci. 2009, 10, 146,  DOI: 10.1186/1471-2202-10-146
    402. 402
      Spathis, A. D.; Asvos, X.; Ziavra, D.; Karampelas, T.; Topouzis, S.; Cournia, Z.; Qing, X.; Alexakos, P.; Smits, L. M.; Dalla, C.; Rideout, H. J.; Schwamborn, J. C.; Tamvakopoulos, C.; Fokas, D.; Vassilatis, D. K. Nurr1:RXRα Heterodimer Activation as Monotherapy for Parkinson’s Disease. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (15), 39994004,  DOI: 10.1073/pnas.1616874114
    403. 403
      Wang, J.; Bi, W.; Zhao, W.; Varghese, M.; Koch, R. J.; Walker, R. H.; Chandraratna, R. A.; Sanders, M. E.; Janesick, A.; Blumberg, B.; Ward, L.; Ho, L.; Pasinetti, G. M. Selective Brain Penetrable Nurr1 Transactivator for Treating Parkinson’s Disease. Oncotarget 2016, 7 (7), 74697479,  DOI: 10.18632/oncotarget.7191
    404. 404
      Loppi, S.; Kolosowska, N.; Kärkkäinen, O.; Korhonen, P.; Huuskonen, M.; Grubman, A.; Dhungana, H.; Wojciechowski, S.; Pomeshchik, Y.; Giordano, M.; Kagechika, H.; White, A.; Auriola, S.; Koistinaho, J.; Landreth, G.; Hanhineva, K.; Kanninen, K.; Malm, T. HX600, a Synthetic Agonist for RXR-Nurr1 Heterodimer Complex, Prevents Ischemia-Induced Neuronal Damage. Brain, Behav., Immun. 2018, 73, 670681,  DOI: 10.1016/j.bbi.2018.07.021
    405. 405
      Jeon, S. G.; Yoo, A.; Chun, D. W.; Hong, S. B.; Chung, H.; Kim, J.-I.; Moon, M. The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-Related Pathogenesis. Aging Dis. 2020, 11 (3), 705724,  DOI: 10.14336/AD.2019.0718
    406. 406
      Terzioglu-Usak, S.; Negis, Y.; Karabulut, D. S.; Zaim, M.; Isik, S. Cellular Model of Alzheimer’s Disease: Aβ1–42 Peptide Induces Amyloid Deposition and a Decrease in Topo Isomerase IIβ and Nurr1 Expression. Curr. Alzheimer Res. 2017, 14 (6), 636644,  DOI: 10.2174/1567205014666170117103217
    407. 407
      Parra-Damas, A.; Valero, J.; Chen, M.; España, J.; Martín, E.; Ferrer, I.; Rodríguez-Alvarez, J.; Saura, C. A. Crtc1 Activates a Transcriptional Program Deregulated at Early Alzheimer’s Disease-Related Stages. J. Neurosci. 2014, 34 (17), 57765787,  DOI: 10.1523/JNEUROSCI.5288-13.2014
    408. 408
      Moon, M.; Jeong, I.; Kim, C.-H.; Kim, J.; Lee, P. K. J.; Mook-Jung, I.; Leblanc, P.; Kim, K.-S. Correlation between Orphan Nuclear Receptor Nurr1 Expression and Amyloid Deposition in 5XFAD Mice, an Animal Model of Alzheimer’s Disease. J. Neurochem. 2015, 132 (2), 254262,  DOI: 10.1111/jnc.12935
    409. 409
      Moon, M.; Jung, E. S.; Jeon, S. G.; Cha, M.-Y.; Jang, Y.; Kim, W.; Lopes, C.; Mook-Jung, I.; Kim, K.-S. Nurr1 (NR4A2) Regulates Alzheimer’s Disease-Related Pathogenesis and Cognitive Function in the 5XFAD Mouse Model. Aging Cell 2019, 18 (1), e12866,  DOI: 10.1111/acel.12866
    410. 410
      Montarolo, F.; Raffaele, C.; Perga, S.; Martire, S.; Finardi, A.; Furlan, R.; Hintermann, S.; Bertolotto, A. Effects of Isoxazolo-Pyridinone 7e, a Potent Activator of the Nurr1 Signaling Pathway, on Experimental Autoimmune Encephalomyelitis in Mice. PLoS One 2014, 9 (9), e108791,  DOI: 10.1371/journal.pone.0108791
    411. 411
      Montarolo, F.; Perga, S.; Martire, S.; Bertolotto, A. Nurr1 Reduction Influences the Onset of Chronic EAE in Mice. Inflammation Res. 2015, 64 (11), 841844,  DOI: 10.1007/s00011-015-0871-4
    412. 412
      Raveney, B. J. E.; Oki, S.; Yamamura, T. Nuclear Receptor NR4A2 Orchestrates Th17 Cell-Mediated Autoimmune Inflammation via IL-21 Signalling. PLoS One 2013, 8 (2), e56595,  DOI: 10.1371/journal.pone.0056595
    413. 413
      Park, T.-Y.; Jang, Y.; Kim, W.; Shin, J.; Toh, H. T.; Kim, C.-H.; Yoon, H. S.; Leblanc, P.; Kim, K.-S. Chloroquine Modulates Inflammatory Autoimmune Responses through Nurr1 in Autoimmune Diseases. Sci. Rep. 2019, 9, 15559,  DOI: 10.1038/s41598-019-52085-w
    414. 414
      Willems, S.; Ohrndorf, J.; Kilu, W.; Heering, J.; Merk, D. Fragment-like Chloroquinolineamines Activate the Orphan Nuclear Receptor Nurr1 and Elucidate Activation Mechanisms. J. Med. Chem. 2021, 64 (5), 26592668,  DOI: 10.1021/acs.jmedchem.0c01779
    415. 415
      de Vera, I. M. S.; Giri, P. K.; Munoz-Tello, P.; Brust, R.; Fuhrmann, J.; Matta-Camacho, E.; Shang, J.; Campbell, S.; Wilson, H. D.; Granados, J.; Gardner, W. J. J.; Creamer, T. P.; Solt, L. A.; Kojetin, D. J. Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1. ACS Chem. Biol. 2016, 11 (7), 17951799,  DOI: 10.1021/acschembio.6b00037
    416. 416
      de Vera, I. M. S.; Munoz-Tello, P.; Zheng, J.; Dharmarajan, V.; Marciano, D. P.; Matta-Camacho, E.; Giri, P. K.; Shang, J.; Hughes, T. S.; Rance, M.; Griffin, P. R.; Kojetin, D. J. Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1. Structure 2019, 27 (1), 6677,  DOI: 10.1016/j.str.2018.10.002
    417. 417
      Windshügel, B. Structural Insights into Ligand-Binding Pocket Formation in Nurr1 by Molecular Dynamics Simulations. J. Biomol. Struct. Dyn. 2019, 37 (17), 46514657,  DOI: 10.1080/07391102.2018.1559099
    418. 418
      Lesuisse, D.; Malanda, A.; Peyronel, J. F.; Evanno, Y.; Lardenois, P.; De-Peretti, D.; Abécassis, P.-Y.; Barnéoud, P.; Brunel, P.; Burgevin, M.-C.; Cegarra, C.; Auger, F.; Dommergue, A.; Lafon, C.; Even, L.; Tsi, J.; Luc, T. P. H.; Almario, A.; Olivier, A.; Castel, M.-N.; Taupin, V.; Rooney, T.; Vigé, X. Development of a Novel NURR1/NOT Agonist from Hit to Lead and Candidate for the Potential Treatment of Parkinson’s Disease. Bioorg. Med. Chem. Lett. 2019, 29 (7), 929932,  DOI: 10.1016/j.bmcl.2019.01.024
    419. 419
      Almario Garcia, A.; Lardenois, P.; Olivier, A. Derivatives of 2-Aryl-6-Phenyl-Imid Azo [1, 2-α]Pyridines, Their Preparation and Their Therapeutic Use. WO2008/034974A1. Sanofi-Aventis, 2008.
    420. 420
      Malanda, A.; Abécassis, P.-Y.; Barnéoud, P.; Brunel, P.; Taupin, V.; Vigé, X.; Lesuisse, D. Data on Synthesis, ADME and Pharmacological Properties and Early Safety Pharmacology Evaluation of a Series of Novel NURR1/NOT Agonist Potentially Useful for the Treatment of Parkinson’s Disease. Data Br. 2019, 27, 104057,  DOI: 10.1016/j.dib.2019.104057
    421. 421
      Dubois, C.; Hengerer, B.; Mattes, H. Identification of a Potent Agonist of the Orphan Nuclear Receptor Nurr1. ChemMedChem 2006, 1 (9), 955958,  DOI: 10.1002/cmdc.200600078
    422. 422
      Hintermann, S.; Chiesi, M.; von Krosigk, U.; Mathé, D.; Felber, R.; Hengerer, B. Identification of a Series of Highly Potent Activators of the Nurr1 Signaling Pathway. Bioorg. Med. Chem. Lett. 2007, 17 (1), 193196,  DOI: 10.1016/j.bmcl.2006.09.062
    423. 423
      Li, X.; Lee, S.-O.; Safe, S. Structure-Dependent Activation of NR4A2 (Nurr1) by 1,1-Bis(3′- Indolyl)-1-(Aromatic)Methane Analogs in Pancreatic Cancer Cells. Biochem. Pharmacol. 2012, 83 (10), 14451455,  DOI: 10.1016/j.bcp.2012.02.021
    424. 424
      Inamoto, T.; Papineni, S.; Chintharlapalli, S.; Cho, S. D.; Safe, S.; Kamat, A. M. 1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane Activates the Orphan Nuclear Receptor Nurr1 and Inhibits Bladder Cancer Growth. Mol. Cancer Ther. 2008, 7 (12), 38253833,  DOI: 10.1158/1535-7163.MCT-08-0730
    425. 425
      De Miranda, B. R.; Popichak, K. A.; Hammond, S. L.; Miller, J. A.; Safe, S.; Tjalkens, R. B. Novel Para-Phenyl Substituted Diindolylmethanes Protect against MPTP Neurotoxicity and Suppress Glial Activation in a Mouse Model of Parkinson’s Disease. Toxicol. Sci. 2015, 143 (2), 360373,  DOI: 10.1093/toxsci/kfu236
    426. 426
      Hammond, S. L.; Safe, S.; Tjalkens, R. B. A Novel Synthetic Activator of Nurr1 Induces Dopaminergic Gene Expression and Protects against 6-Hydroxydopamine Neurotoxicity in Vitro. Neurosci. Lett. 2015, 607, 8389,  DOI: 10.1016/j.neulet.2015.09.015
    427. 427
      Hammond, S. L.; Tjalkens, R. B.; Safe, S.; Richman, E. H.; Backos, D. S.; Li, X.; Hunt, L. G.; Chong, E.; Popichak, K. A.; Damale, P. The Nurr1 Ligand,1,1-Bis(3′-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism. J. Pharmacol. Exp. Ther. 2018, 365 (3), 636651,  DOI: 10.1124/jpet.117.246389
    428. 428
      Karki, K.; Li, X.; Jin, U.-H.; Mohankumar, K.; Zarei, M.; Michelhaugh, S. K.; Mittal, S.; Tjalkens, R.; Safe, S. Nuclear Receptor 4A2 (NR4A2) Is a Druggable Target for Glioblastomas. J. Neuro-Oncol. 2020, 146 (1), 2539,  DOI: 10.1007/s11060-019-03349-y
    429. 429
      De Miranda, B. R.; Miller, J. A.; Hansen, R. J.; Lunghofer, P. J.; Safe, S.; Gustafson, D. L.; Colagiovanni, D.; Tjalkens, R. B. Neuroprotective Efficacy and Pharmacokinetic Behavior of Novel Anti-Inflammatory Para-Phenyl Substituted Diindolylmethanes in a Mouse Mdel of Parkinson’s Disease. J. Pharmacol. Exp. Ther. 2013, 345 (1), 125138,  DOI: 10.1124/jpet.112.201558
    430. 430
      Hibino, S.; Chikuma, S.; Kondo, T.; Ito, M.; Nakatsukasa, H.; Omata-Mise, S.; Yoshimura, A. Inhibition of Nr4a Receptors Enhances Antitumor Immunity by Breaking Treg-Mediated Immune Tolerance. Cancer Res. 2018, 78 (11), 30273040,  DOI: 10.1158/0008-5472.CAN-17-3102
    431. 431
      Komiya, T.; Yamamoto, S.; Roy, A.; McDonald, P.; Perez, R. P. Drug Screening to Target Nuclear Orphan Receptor NR4A2 for Cancer Therapeutics. Transl. Lung Cancer Res. 2017, 6 (5), 600610,  DOI: 10.21037/tlcr.2017.07.02
    432. 432
      Pan, T.; Xie, W.; Jankovic, J.; Le, W. Biological Effects of Pramipexole on Dopaminergic Neuron-Associated Genes: Relevance to Neuroprotection. Neurosci. Lett. 2005, 377 (2), 106109,  DOI: 10.1016/j.neulet.2004.11.080
    433. 433
      Hedya, S. A.; Safar, M. M.; Bahgat, A. K. Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model. Mol. Neurobiol. 2018, 55 (9), 75797587,  DOI: 10.1007/s12035-018-0923-1
    434. 434
      Ham, A.; Lee, H. J.; Hong, S. S.; Lee, D.; Mar, W. Moracenin D from Mori Cortex Radicis Protects SH-SY5Y Cells against Dopamine-Induced Cell Death by Regulating Nurr1 and α-Synuclein Expression. Phytother. Res. 2012, 26 (4), 620624,  DOI: 10.1002/ptr.3592
    435. 435
      Wallén-Mackenzie, Å.; De Urquiza, A. M.; Petersson, S.; Rodriguez, F. J.; Friling, S.; Wagner, J.; Ordentlich, P.; Lengqvist, J.; Heyman, R. A.; Arenas, E.; Perlmann, T. Nurr1-RXR Heterodimers Mediate RXR Ligand-Induced Signaling in Neuronal Cells. Genes Dev. 2003, 17 (24), 30363047,  DOI: 10.1101/gad.276003
    436. 436
      Morita, K.; Kawana, K.; Sodeyama, M.; Shimomura, I.; Kagechika, H.; Makishima, M. Selective Allosteric Ligand Activation of the Retinoid X Receptor Heterodimers of NGFI-B and Nurr1. Biochem. Pharmacol. 2005, 71 (1–2), 98107,  DOI: 10.1016/j.bcp.2005.10.017
    437. 437
      Ishizawa, M.; Kagechika, H.; Makishima, M. NR4A Nuclear Receptors Mediate Carnitine Palmitoyltransferase 1A Gene Expression by the Rexinoid HX600. Biochem. Biophys. Res. Commun. 2012, 418 (4), 780785,  DOI: 10.1016/j.bbrc.2012.01.102
    438. 438
      Sundén, H.; Schäfer, A.; Scheepstra, M.; Leysen, S.; Malo, M.; Ma, J.-N.; Burstein, E. S.; Ottmann, C.; Brunsveld, L.; Olsson, R. Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation. J. Med. Chem. 2016, 59 (3), 12321238,  DOI: 10.1021/acs.jmedchem.5b01702
    439. 439
      Scheepstra, M.; Andrei, S. A.; de Vries, R. M. J. M.; Meijer, F. A.; Ma, J.-N.; Burstein, E. S.; Olsson, R.; Ottmann, C.; Milroy, L.-G.; Brunsveld, L. Ligand Dependent Switch from RXR Homo- to RXR-NURR1 Heterodimerization. ACS Chem. Neurosci. 2017, 8 (9), 20652077,  DOI: 10.1021/acschemneuro.7b00216
    440. 440
      McFarland, K.; Spalding, T. A.; Hubbard, D.; Ma, J.-N.; Olsson, R.; Burstein, E. S. Low Dose Bexarotene Treatment Rescues Dopamine Neurons and Restores Behavioral Function in Models of Parkinson’s Disease. ACS Chem. Neurosci. 2013, 4 (11), 14301438,  DOI: 10.1021/cn400100f
    441. 441
      Pönniö, T.; Conneely, O. M. Nor-1 Regulates Hippocampal Axon Guidance, Pyramidal Cell Survival, and Seizure Susceptibility. Mol. Cell. Biol. 2004, 24 (20), 90709078,  DOI: 10.1128/MCB.24.20.9070-9078.2004
    442. 442
      Ferrán, B.; Martí-Pàmies, I.; Alonso, J.; Rodríguez-calvo, R.; Aguiló, S.; Vidal, F.; Rodríguez, C.; Martínez-gonzález, J. The Nuclear Receptor NOR-1 Regulates the Small Muscle Protein, X-Linked (SMPX) and Myotube Differentiation. Sci. Rep. 2016, 6, 25944,  DOI: 10.1038/srep25944
    443. 443
      Kon, T.; Miki, Y.; Tanji, K.; Mori, F.; Tomiyama, M.; Toyoshima, Y.; Kakita, A.; Takahashi, H.; Utsumi, J.; Sasaki, H.; Wakabayashi, K. Localization of Nuclear Receptor Subfamily 4, Group A, Member 3 (NR4A3) in Lewy Body Disease and Multiple System Atrophy. Neuropathology 2015, 35 (6), 503509,  DOI: 10.1111/neup.12210
    444. 444
      Maheux, J.; Ethier, I.; Rouillard, C.; Levesque, D. Induction Patterns of Transcription Factors of the Nur Family (Nurr1, Nur77, and Nor −1) by Typical and Atypical Antipsychotics in the Mouse Brain : Implication for Their Mechanism of Action. J. Pharmacol. Exp. Ther. 2005, 313 (1), 460473,  DOI: 10.1124/jpet.104.080184
    445. 445
      DeYoung, R. A.; Baker, J. C.; Cado, D.; Winoto, A. The Orphan Steroid Receptor Nur77 Family Member Nor-1 Is Essential for Early Mouse Embryogenesis. J. Biol. Chem. 2003, 278 (47), 4710447109,  DOI: 10.1074/jbc.M307496200
    446. 446
      Chio, C.-C.; Wei, L.; Chen, T. G.; Lin, C.-M.; Shieh, J.-P.; Yeh, P.-S.; Chen, R.-M. Neuron-Derived Orphan Receptor 1 Transduces Survival Signals in Neuronal Cells in Response to Hypoxia-Induced Apoptotic Insults. J. Neurosurg. 2016, 124 (6), 16541664,  DOI: 10.3171/2015.6.JNS1535
    447. 447
      Kagaya, S.; Ohkura, N.; Tsukada, T.; Miyagawa, M.; Sugita, Y.; Tsujimoto, G.; Matsumoto, K.; Saito, H.; Hashida, R. Prostaglandin A 2 Acts as a Transactivator for NOR1 (NR4A3) within the Nuclear Receptor Superfamily. Biol. Pharm. Bull. 2005, 28 (9), 16031607,  DOI: 10.1248/bpb.28.1603
    448. 448
      Eyster, K. M. The Estrogen Receptors: An Overview from Different Perspectives. In Methods in Molecular Biology; Humana Press Inc., 2016; Vol. 1366, pp 110.
    449. 449
      Dahlman-Wright, K.; Cavailles, V.; Fuqua, S. A.; Jordan, V. C.; Katzenellenbogen, J. A.; Korach, K. S.; Maggi, A.; Muramatsu, M.; Parker, M. G.; Gustafsson, J.-Å. International Union of Pharmacology. LXIV. Estrogen Receptors. Pharmacol. Rev. 2006, 58 (4), 773781,  DOI: 10.1124/pr.58.4.8
    450. 450
      Hewitt, S. C.; Korach, K. S. Estrogen Receptors: New Directions in the New Millennium. Endocr. Rev. 2018, 39 (5), 664675,  DOI: 10.1210/er.2018-00087
    451. 451
      Dupont, S.; Krust, A.; Gansmuller, A.; Dierich, A.; Chambon, P.; Mark, M. Effect of Single and Compound Knockouts of Estrogen Receptors Alpha (ERalpha) and Beta (ERbeta) on Mouse Reproductive Phenotypes. Development 2000, 127 (19), 42774291,  DOI: 10.1242/dev.127.19.4277
    452. 452
      Lan, Y.-L.; Zhao, J.; Li, S. Update on the Neuroprotective Effect of Estrogen Receptor Alpha Against Alzheimer’s Disease. J. Alzheimer's Dis. 2015, 43 (4), 11371148,  DOI: 10.3233/JAD-141875
    453. 453
      Chakrabarti, M.; Haque, A.; Banik, N. L.; Nagarkatti, P.; Nagarkatti, M.; Ray, S. K. Estrogen Receptor Agonists for Attenuation of Neuroinflammation and Neurodegeneration. Brain Res. Bull. 2014, 109, 2231,  DOI: 10.1016/j.brainresbull.2014.09.004
    454. 454
      Pike, C. J.; Carroll, J. C.; Rosario, E. R.; Barron, A. M. Protective Actions of Sex Steroid Hormones in Alzheimer’s Disease. Frontiers in Neuroendocrinology 2009, 30 (2), 239258,  DOI: 10.1016/j.yfrne.2009.04.015
    455. 455
      Boada, M.; Antunez, C.; López-Arrieta, J.; Caruz, A.; Moreno-Rey, C.; Ramírez-Lorca, R.; Morón, F. J.; Hernández, I.; Mauleón, A.; Rosende-Roca, M.; Martínez-Lage, P.; Marín, J.; Tárraga, L.; Alegret, M.; Pedrajas, J. R.; Urda, N.; Royo, J. L.; Saez, M. E.; Gayán, J.; González-Pérez, A.; Real, L. M.; Ruiz, A.; Galán, J. J. Estrogen Receptor Alpha Gene Variants Are Associated with Alzheimer’s Disease. Neurobiol. Aging 2012, 33 (1), 198.e15198.e24,  DOI: 10.1016/j.neurobiolaging.2010.06.016
    456. 456
      Goodman, Y.; Bruce, A. J.; Cheng, B.; Mattson, M. P. Estrogens Attenuate and Corticosterone Exacerbates Excitotoxicity, Oxidative Injury, and Amyloid β-Peptide Toxicity in Hippocampal Neurons. J. Neurochem. 1996, 66 (5), 18361844,  DOI: 10.1046/j.1471-4159.1996.66051836.x
    457. 457
      Green, P. S.; Gridley, K. E.; Simpkins, J. W. Estradiol Protects against β-Amyloid (25–35)-Induced Toxicity in SK-N-SH Human Neuroblastoma Cells. Neurosci. Lett. 1996, 218 (3), 165168,  DOI: 10.1016/S0304-3940(96)13148-7
    458. 458
      Behl, C.; Widmann, M.; Trapp, T.; Holsboer, F. 17-β Estradiol Protects Neurons from Oxidative Stress-Induced Cell Death in Vitro. Biochem. Biophys. Res. Commun. 1995, 216 (2), 473482,  DOI: 10.1006/bbrc.1995.2647
    459. 459
      Singer, C. A.; Rogers, K. L.; Strickland, T. M.; Dorsa, D. M. Estrogen Protects Primary Cortical Neurons from Glutamate Toxicity. Neurosci. Lett. 1996, 212 (1), 1316,  DOI: 10.1016/0304-3940(96)12760-9
    460. 460
      Zhang, Q.-G.; Raz, L.; Wang, R.; Han, D.; De Sevilla, L.; Yang, F.; Vadlamudi, R. K.; Brann, D. W. Estrogen Attenuates Ischemic Oxidative Damage Via an Estrogen Receptor α-Mediated Inhibition of NADPH Oxidase Activation. J. Neurosci. 2009, 29 (44), 1382313836,  DOI: 10.1523/JNEUROSCI.3574-09.2009
    461. 461
      Spampinato, S. F.; Molinaro, G.; Merlo, S.; Iacovelli, L.; Caraci, F.; Battaglia, G.; Nicoletti, F.; Bruno, V.; Sortino, M. A. Estrogen Receptors and Type 1 Metabotropic Glutamate Receptors Are Interdependent in Protecting Cortical Neurons against β-Amyloid Toxicity. Mol. Pharmacol. 2012, 81 (1), 1220,  DOI: 10.1124/mol.111.074021
    462. 462
      Pike, C. J. Estrogen Modulates Neuronal Bcl-XL Expression and β-Amyloid-Induced Apoptosis: Relevance to Alzheimer’s Disease. J. Neurochem. 1999, 72 (4), 15521563,  DOI: 10.1046/j.1471-4159.1999.721552.x
    463. 463
      Yao, M.; Nguyen, T.-V. V.; Pike, C. J. Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against β-Amyloid Peptide-Induced Neuronal Death. J. Neurosci. 2007, 27 (6), 14221433,  DOI: 10.1523/JNEUROSCI.2382-06.2007
    464. 464
      Zhao, L.; Wu, T.-W.; Brinton, R. D. Estrogen Receptor Subtypes Alpha and Beta Contribute to Neuroprotection and Increased Bcl-2 Expression in Primary Hippocampal Neurons. Brain Res. 2004, 1010 (1–2), 2234,  DOI: 10.1016/j.brainres.2004.02.066
    465. 465
      Suwanna, N.; Thangnipon, W.; Soi-ampornkul, R. Neuroprotective Effects of Diarylpropionitrile against β-Amyloid Peptide-Induced Neurotoxicity in Rat Cultured Cortical Neurons. Neurosci. Lett. 2014, 578, 4449,  DOI: 10.1016/j.neulet.2014.06.029
    466. 466
      Mateos, L.; Persson, T.; Kathozi, S.; Gil-Bea, F. J.; Cedazo-Minguez, A. Estrogen Protects against Amyloid-β Toxicity by Estrogen Receptor α-Mediated Inhibition of Daxx Translocation. Neurosci. Lett. 2012, 506 (2), 245250,  DOI: 10.1016/j.neulet.2011.11.016
    467. 467
      Witty, C. F.; Gardella, L. P.; Perez, M. C.; Daniel, J. M. Short-Term Estradiol Administration in Aging Ovariectomized Rats Provides Lasting Benefits for Memory and the Hippocampus: A Role for Insulin-like Growth Factor-I. Endocrinology 2013, 154 (2), 842852,  DOI: 10.1210/en.2012-1698
    468. 468
      Azcoitia, I.; Sierra, A.; Garcia-Segura, L. M. Neuroprotective Effects of Estradiol in the Adult Rat Hippocampus: Interaction with Insulin-like Growth Factor-I Signalling. J. Neurosci. Res. 1999, 58 (6), 815822,  DOI: 10.1002/(SICI)1097-4547(19991215)58:6<815::AID-JNR8>3.0.CO;2-R
    469. 469
      Rosario, E. R.; Ramsden, M.; Pike, C. J. Progestins Inhibit the Neuroprotective Effects of Estrogen in Rat Hippocampus. Brain Res. 2006, 1099 (1), 206210,  DOI: 10.1016/j.brainres.2006.03.127
    470. 470
      Carroll, J. C.; Rosario, E. R.; Pike, C. J. Progesterone Blocks Estrogen Neuroprotection from Kainate in Middle-Aged Female Rats. Neurosci. Lett. 2008, 445 (3), 229232,  DOI: 10.1016/j.neulet.2008.09.010
    471. 471
      Kim, H.; Bang, O. Y.; Jung, M. W.; Ha, S. D.; Hong, H. S.; Huh, K.; Kim, S. U.; Mook-Jung, I. Neuroprotective Effects of Estrogen against Beta-Amyloid Toxicity Are Mediated by Estrogen Receptors in Cultured Neuronal Cells. Neurosci. Lett. 2001, 302 (1), 5862,  DOI: 10.1016/S0304-3940(01)01659-7
    472. 472
      Benvenuti, S.; Luciani, P.; Vannelli, G. B.; Gelmini, S.; Franceschi, E.; Serio, M.; Peri, A. Estrogen and Selective Estrogen Receptor Modulators Exert Neuroprotective Effects and Stimulate the Expression of Selective Alzheimer’s Disease Indicator-1, a Recently Discovered Antiapoptotic Gene, in Human Neuroblast Long-Term Cell Cultures. J. Clin. Endocrinol. Metab. 2005, 90 (3), 17751782,  DOI: 10.1210/jc.2004-0066
    473. 473
      Mize, A. L.; Young, L. J.; Alper, R. H. Uncoupling of 5-HT1A Receptors in the Brain by Estrogens: Regional Variations in Antagonism by ICI 182,780. Neuropharmacology 2003, 44 (5), 584591,  DOI: 10.1016/S0028-3908(03)00044-3
    474. 474
      Cordey, M.; Pike, C. J. Neuroprotective Properties of Selective Estrogen Receptor Agonists in Cultured Neurons. Brain Res. 2005, 1045 (1–2), 217223,  DOI: 10.1016/j.brainres.2005.03.032
    475. 475
      Fitzpatrick, J. L.; Mize, A. L.; Wade, C. B.; Harris, J. A.; Shapiro, R. A.; Dorsa, D. M. Estrogen-Mediated Neuroprotection against β-Amyloid Toxicity Requires Expression of Estrogen Receptor α or β and Activation of the MAPK Pathway. J. Neurochem. 2002, 82 (3), 674682,  DOI: 10.1046/j.1471-4159.2002.01000.x
    476. 476
      Tiwari-Woodruff, S.; Morales, L. B. J.; Lee, R.; Voskuhl, R. R. Differential Neuroprotective and Antiinflammatory Effects of Estrogen Receptor (ER)α and ERβ Ligand Treatment. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (37), 1481314818,  DOI: 10.1073/pnas.0703783104
    477. 477
      Bourque, M.; Dluzen, D. E.; Di Paolo, T. Signaling Pathways Mediating the Neuroprotective Effects of Sex Steroids and SERMs in Parkinson’s Disease. Front. Neuroendocrinol 2012, 33 (2), 169178,  DOI: 10.1016/j.yfrne.2012.02.003
    478. 478
      Zhao, L.; Brinton, R. D. Estrogen Receptor α and β Differentially Regulate Intracellular Ca2+ Dynamics Leading to ERK Phosphorylation and Estrogen Neuroprotection in Hippocampal Neurons. Brain Res. 2007, 1172, 4859,  DOI: 10.1016/j.brainres.2007.06.092
    479. 479
      Yang, L.-C.; Zhang, Q.-G.; Zhou, C.-F.; Yang, F.; Zhang, Y.-D.; Wang, R.-M.; Brann, D. W. Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus. PLoS One 2010, 5 (5), e9851,  DOI: 10.1371/journal.pone.0009851
    480. 480
      Long, J.; He, P.; Shen, Y.; Li, R. New Evidence of Mitochondria Dysfunction in the Female Alzheimer’s Disease Brain: Deficiency of Estrogen Receptor-β. J. Alzheimer's Dis. 2012, 30 (3), 545558,  DOI: 10.3233/JAD-2012-120283
    481. 481
      Xu, H.; Gouras, G. K.; Greenfield, J. P.; Vincent, B.; Naslund, J.; Mazzarelli, L.; Fried, G.; Jovanovic, J. N.; Seeger, M.; Relkin, N. R.; Liao, F.; Checler, F.; Buxbaum, J. D.; Chait, B. T.; Thinakaran, G.; Sisodia, S. S.; Wang, R.; Greengard, P.; Gandy, S. Estrogen Reduces Neuronal Generation of Alzheimer β-Amyloid Peptides. Nat. Med. 1998, 4 (4), 447451,  DOI: 10.1038/nm0498-447
    482. 482
      Watters, J. J.; Campbell, J. S.; Cunningham, M. J.; Krebs, E. G.; Dorsa, D. M. Rapid MembraneEffects of Steroids in Neuroblastoma Cells: Effects of Estrogen on Mitogen Activated Protein Kinase Signalling Cascade and c-Fos Immediate Early Gene Transcription. Endocrinology 1997, 138 (9), 40304033,  DOI: 10.1210/endo.138.9.5489
    483. 483
      Manthey, D.; Heck, S.; Engert, S.; Behl, C. Estrogen Induces a Rapid Secretion of Amyloid β Precursor Protein via the Mitogen-Activated Protein Kinase Pathway. Eur. J. Biochem. 2001, 268 (15), 42854291,  DOI: 10.1046/j.1432-1327.2001.02346.x
    484. 484
      Li, R.; Shen, Y.; Yang, L.-B.; Lue, L.-F.; Finch, C.; Rogers, J. Estrogen Enhances Uptake of Amyloid β-Protein by Microglia Derived from the Human Cortex. J. Neurochem. 2000, 75 (4), 14471454,  DOI: 10.1046/j.1471-4159.2000.0751447.x
    485. 485
      Harris-White, M. E.; Chu, T.; Miller, S. A.; Simmons, M.; Teter, B.; Nash, D.; Cole, G. M.; Frautschy, S. A. Estrogen (E2) and Glucocorticoid (Gc) Effects on Microglia and Aβ Clearance in Vitro and in Vivo. Neurochem. Int. 2001, 39 (5–6), 435448,  DOI: 10.1016/S0197-0186(01)00051-1
    486. 486
      Bruce-Keller, A. J.; Keeling, J. L.; Keller, J. N.; Huang, F. F.; Camondola, S.; Mattson, M. P. Antiinflammatory Effects of Estrogen on Microglial Activation. Endocrinology 2000, 141 (10), 36463656,  DOI: 10.1210/endo.141.10.7693
    487. 487
      George, S.; Petit, G. H.; Gouras, G. K.; Brundin, P.; Olsson, R. Nonsteroidal Selective Androgen Receptor Modulators and Selective Estrogen Receptor β Agonists Moderate Cognitive Deficits and Amyloid-β Levels in a Mouse Model of Alzheimer’s Disease. ACS Chem. Neurosci. 2013, 4 (12), 15371548,  DOI: 10.1021/cn400133s
    488. 488
      Yue, X.; Lu, M.; Lancaster, T.; Cao, P.; Honda, S. I.; Staufenbiel, M.; Harada, N.; Zhong, Z.; Shen, Y.; Li, R. Brain Estrogen Deficiency Accelerates Aβ Plaque Formation in an Alzheimer’s Disease Animal Model. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (52), 1919819203,  DOI: 10.1073/pnas.0505203102
    489. 489
      Tanzi, R. E.; Moir, R. D.; Wagner, S. L. Clearance of Alzheimer’s Aβ Peptide: The Many Roads to Perdition. Neuron 2004, 43, 605608,  DOI: 10.1016/j.neuron.2004.08.024
    490. 490
      Wei, Y.; Zhou, J.; Wu, J.; Huang, J. ERβ Promotes Aβ Degradation via the Modulation of Autophagy. Cell Death Dis. 2019, 10 (8), 565,  DOI: 10.1038/s41419-019-1786-8
    491. 491
      Hayes, M. T. Parkinson’s Disease and Parkinsonism. American Journal of Medicine 2019, 132 (7), 802807,  DOI: 10.1016/j.amjmed.2019.03.001.
    492. 492
      Popat, R. A.; Van Den Eeden, S. K.; Tanner, C. M.; McGuire, V.; Bernstein, A. L.; Bloch, D. A.; Leimpeter, A.; Nelson, L. M. Effect of Reproductive Factors and Postmenopausal Hormone Use on the Risk of Parkinson Disease. Neurology 2005, 65 (3), 383390,  DOI: 10.1212/01.wnl.0000171344.87802.94
    493. 493
      Wang, P.; Li, J.; Qiu, S.; Wen, H.; Du, J. Hormone Replacement Therapy and Parkinson’s Disease Risk in Women: A Meta-Analysis of 14 Observational Studies. Neuropsychiatr. Dis. Treat. 2015, 11, 5966,  DOI: 10.2147/NDT.S69918
    494. 494
      Currie, L. J.; Harrison, M. B.; Trugman, J. M.; Bennett, J. P.; Wooten, G. F. Postmenopausal Estrogen Use Affects Risk for Parkinson Disease. Arch. Neurol. 2004, 61 (6), 886888,  DOI: 10.1001/archneur.61.6.886
    495. 495
      Bourque, M.; Morissette, M.; Di Paolo, T. Repurposing Sex Steroids and Related Drugs as Potential Treatment for Parkinson’s Disease. Neuropharmacology 2019, 147, 3754
    496. 496
      Blanchet, P. J.; Fang, J.; Hyland, K.; Arnold, L. A.; Mouradian, M. M.; Chase, T. N. Short-Term Effects of High-Dose 17β-Estradiol in Postmenopausal PD Patients: A Crossover Study. Neurology 1999, 53 (1), 9195,  DOI: 10.1212/WNL.53.1.91
    497. 497
      Strijks, E.; Kremer, J. A. M.; Horstink, M. W. I. M. Effects of Female Sex Steroids on Parkinson’s Disease in Postmenopausal Women. Clin. Neuropharmacol. 1999, 22 (2), 9397,  DOI: 10.1097/00002826-199903000-00005
    498. 498
      Dluzen, D. E.; McDermott, J. L.; Anderson, L. I. Tamoxifen Eliminates Estrogen’s Neuroprotective Effect upon MPTP-Induced Neurotoxicity of the Nigrostriatal Dopaminergic System. Neurotoxic. Res. 2001, 3 (3), 291300,  DOI: 10.1007/BF03033268
    499. 499
      Morissette, M.; Sweidi, S. Al; Callier, S.; Di Paolo, T. Estrogen and SERM Neuroprotection in Animal Models of Parkinson’s Disease. Mol. Cell. Endocrinol. 2008, 290 (1–2), 6069,  DOI: 10.1016/j.mce.2008.04.008
    500. 500
      Baraka, A. M.; Korish, A. A.; Soliman, G. A.; Kamal, H. The Possible Role of Estrogen and Selective Estrogen Receptor Modulators in a Rat Model of Parkinson’s Disease. Life Sci. 2011, 88 (19–20), 879885,  DOI: 10.1016/j.lfs.2011.03.010
    501. 501
      McFarland, K.; Price, D. L.; Davis, C. N.; Ma, J.-N.; Bonhaus, D. W.; Burstein, E. S.; Olsson, R. AC-186, a Selective Nonsteroidal Estrogen Receptor β Agonist, Shows Gender Specific Neuroprotection in a Parkinson’s Disease Rat Model. ACS Chem. Neurosci. 2013, 4 (9), 12491255,  DOI: 10.1021/cn400132u
    502. 502
      Sierra, A.; Gottfried-Blackmore, A.; Milner, T. A.; McEwen, B. S.; Bulloch, K. Steroid Hormone Receptor Expression and Function in Microglia. Glia 2008, 56 (6), 659674,  DOI: 10.1002/glia.20644
    503. 503
      Barreto, G.; Santos-Galindo, M.; Diz-Chaves, Y.; Pernía, O.; Carrero, P.; Azcoitia, I.; Garcia-Segura, L. M. Selective Estrogen Receptor Modulators Decrease Reactive Astrogliosis in the Injured Brain: Effects of Aging and Prolonged Depletion of Ovarian Hormones. Endocrinology 2009, 150 (11), 50105015,  DOI: 10.1210/en.2009-0352
    504. 504
      Maglione, A.; Rolla, S.; De Mercanti, S. F.; Cutrupi, S.; Clerico, M. The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View. Cells 2019, 8 (10), 1280,  DOI: 10.3390/cells8101280
    505. 505
      Villa, A.; Vegeto, E.; Poletti, A.; Maggi, A. Estrogens, Neuroinflammation, and Neurodegeneration. Endocrine Reviews 2016, 37 (4), 372402,  DOI: 10.1210/er.2016-1007
    506. 506
      Lewis, D. K.; Johnson, A. B.; Stohlgren, S.; Harms, A.; Sohrabji, F. Effects of Estrogen Receptor Agonists on Regulation of the Inflammatory Response in Astrocytes from Young Adult and Middle-Aged Female Rats. J. Neuroimmunol. 2008, 195 (1–2), 4759,  DOI: 10.1016/j.jneuroim.2008.01.006
    507. 507
      Vegeto, E.; Belcredito, S.; Etteri, S.; Ghisletti, S.; Brusadelli, A.; Meda, C.; Krust, A.; Dupont, S.; Ciana, P.; Chambon, P.; Maggi, A. Estrogen Receptor-α Mediates the Brain Antiinflammatory Activity of Estradiol. Proc. Natl. Acad. Sci. U. S. A. 2003, 100 (16), 96149619,  DOI: 10.1073/pnas.1531957100
    508. 508
      Bebo, B. F.; Fyfe-Johnson, A.; Adlard, K.; Beam, A. G.; Vandenbark, A. A.; Offner, H. Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains. J. Immunol. 2001, 166 (3), 20802089,  DOI: 10.4049/jimmunol.166.3.2080
    509. 509
      Ito, A.; Bebo, B. F.; Matejuk, A.; Zamora, A.; Silverman, M.; Fyfe-Johnson, A.; Offner, H. Estrogen Treatment Down-Regulates TNF-α Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice. J. Immunol. 2001, 167 (1), 542552,  DOI: 10.4049/jimmunol.167.1.542
    510. 510
      Liu, H. Y.; Buenafe, A. C.; Matejuk, A.; Ito, A.; Zamora, A.; Dwyer, J.; Vandenbark, A. A.; Offner, H. Estrogen Inhibition of EAE Involves Effects on Dendritic Cell Function. J. Neurosci. Res. 2002, 70 (2), 238248,  DOI: 10.1002/jnr.10409
    511. 511
      Spence, R. D.; Hamby, M. E.; Umeda, E.; Itoh, N.; Du, S.; Wisdom, A. J.; Cao, Y.; Bondar, G.; Lam, J.; Ao, Y.; Sandoval, F.; Suriany, S.; Sofroniew, M. V.; Voskuhl, R. R. Neuroprotection Mediated through Estrogen Receptor-α in Astrocytes. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (21), 88678872,  DOI: 10.1073/pnas.1103833108
    512. 512
      Kim, S.; Liva, S. M.; Dalal, M. A.; Verity, M. A.; Voskuhl, R. R. Estriol Ameliorates Autoimmune Demyelinating Disease: Implications for Multiple Sclerosis. Neurology 1999, 52 (6), 12301238,  DOI: 10.1212/WNL.52.6.1230
    513. 513
      Spence, R. D.; Wisdom, A. J.; Cao, Y.; Hill, H. M.; Mongerson, C. R. L.; Stapornkul, B.; Itoh, N.; Sofroniew, M. V.; Voskuhl, R. R. Estrogen Mediates Neuroprotection and Anti-Inflammatory Effects during EAE through ERα Signaling on Astrocytes but Not through ERβ Signaling on Astrocytes or Neurons. J. Neurosci. 2013, 33 (26), 1092410933,  DOI: 10.1523/JNEUROSCI.0886-13.2013
    514. 514
      Sicotte, N. L.; Liva, S. M.; Klutch, R.; Pfeiffer, P.; Bouvier, S.; Odesa, S.; Wu, T. C. J.; Voskuhl, R. R. Treatment of Multiple Sclerosis with the Pregnancy Hormone Estriol. Ann. Neurol. 2002, 52 (4), 421428,  DOI: 10.1002/ana.10301
    515. 515
      Vukusic, S.; Ionescu, I.; El-Etr, M.; Schumacher, M.; Baulieu, E. E.; Cornu, C.; Confavreux, C. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART′MUS) Trial: Rationale, Objectives and State of Advancement. J. Neurol. Sci. 2009, 286 (1–2), 114118,  DOI: 10.1016/j.jns.2009.08.056
    516. 516
      Pozzilli, C.; De Giglio, L.; Barletta, V. T.; Marinelli, F.; De Angelis, F.; Gallo, V.; Pagano, V. A.; Marini, S.; Piattella, M. C.; Tomassini, V.; Pantano, P. Oral Contraceptives Combined with Interferon b in Multiple Sclerosis. Neurol. Neuroimmunol. NeuroInflammation 2015, 2 (4), e120,  DOI: 10.1212/NXI.0000000000000120
    517. 517
      Voskuhl, R. R.; Wang, H. J.; Wu, T. C. J.; Sicotte, N. L.; Nakamura, K.; Kurth, F.; Itoh, N.; Bardens, J.; Bernard, J. T.; Corboy, J. R.; Cross, A. H.; Dhib-Jalbut, S.; Ford, C. C.; Frohman, E. M.; Giesser, B.; Jacobs, D.; Kasper, L. H.; Lynch, S.; Parry, G.; Racke, M. K.; Reder, A. T.; Rose, J.; Wingerchuk, D. M.; MacKenzie-Graham, A. J.; Arnold, D. L.; Tseng, C. H.; Elashoff, R. Estriol Combined with Glatiramer Acetate for Women with Relapsing-Remitting Multiple Sclerosis: A Randomised, Placebo-Controlled, Phase 2 Trial. Lancet Neurol. 2016, 15 (1), 3546,  DOI: 10.1016/S1474-4422(15)00322-1
    518. 518
      Rossouw, J. E.; Anderson, G. L.; Prentice, R. L.; LaCroix, A. Z.; Kooperberg, C.; Stefanick, M. L.; Jackson, R. D.; Beresford, S. A. A.; Howard, B. V.; Johnson, K. C.; Kotchen, J. M.; Ockene, J. Risks and Benefits of Estrogen plus Progestin in Healthy Postmenopausal Women: Principal Results from the Women’s Health Initiative Randomized Controlled Trial. JAMA, J. Am. Med. Assoc. 2002, 288 (3), 321333,  DOI: 10.1001/jama.288.3.321
    519. 519
      Paterni, I.; Granchi, C.; Katzenellenbogen, J. A.; Minutolo, F. Estrogen Receptors Alpha (ERα) and Beta (ERβ): Subtype-Selective Ligands and Clinical Potential. Steroids 2014, 90, 1329,  DOI: 10.1016/j.steroids.2014.06.012
    520. 520
      Brzozowski, A. M.; Pike, A. C. W.; Dauter, Z.; Hubbard, R. E.; Bonn, T.; Engström, O.; Öhman, L.; Greene, G. L.; Gustafsson, J.-Å.; Carlquist, M. Molecular Basis of Agonism and Antagonism in the Oestrogen Receptor. Nature 1997, 389 (6652), 753758,  DOI: 10.1038/39645
    521. 521
      Pike, A. C. W.; Brzozowski, A. M.; Hubbard, R. E.; Bonn, T.; Thorsell, A.-G.; Engström, O.; Ljunggren, J.; Gustafsson, J.-Å.; Carlquist, M. Structure of the Ligand-Binding Domain of Oestrogen Receptor Beta in the Presence of a Partial Agonist and a Full Antagonist. EMBO J. 1999, 18 (17), 46084618,  DOI: 10.1093/emboj/18.17.4608
    522. 522
      Shiau, A. K.; Barstad, D.; Radek, J. T.; Meyers, M. J.; Nettles, K. W.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A.; Agard, D. A.; Greene, G. L. Structural Characterization of a Subtype-Selective Ligand Reveals a Novel Mode of Estrogen Receptor Antagonism. Nat. Struct. Biol. 2002, 9 (5), 359364,  DOI: 10.1038/nsb787
    523. 523
      Levenson, A. S.; Craig Jordan, V. The Key to the Antiestrogenic Mechanism of Raloxifene Is Amino Acid 351 (Aspartate) in the Estrogen Receptor. Cancer Res. 1998, 58 (9), 18721875
    524. 524
      Heldring, N.; Pike, A.; Andersson, S.; Matthews, J.; Cheng, G.; Hartman, J.; Tujague, M.; Ström, A.; Treuter, E.; Warner, M.; Gustafsson, J.-Å. Estrogen Receptors: How Do They Signal and What Are Their Targets. Physiol. Rev. 2007, 87 (3), 905931,  DOI: 10.1152/physrev.00026.2006
    525. 525
      Nilsson, S.; Koehler, K. F.; Gustafsson, J.-Å. Development of Subtype-Selective Oestrogen Receptor-Based Therapeutics. Nat. Rev. Drug Discovery 2011, 10 (10), 778792,  DOI: 10.1038/nrd3551
    526. 526
      Jordan, V. C. Antiestrogens and Selective Estrogen Receptor Modulators as Multifunctional Medicines. 1. Receptor Interactions. J. Med. Chem. 2003, 46, 883908,  DOI: 10.1021/jm020449y
    527. 527
      Stauffer, S. R.; Coletta, C. J.; Tedesco, R.; Nishiguchi, G.; Carlson, K.; Sun, J.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Pyrazole Ligands: Structure - Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists. J. Med. Chem. 2000, 43 (26), 49344947,  DOI: 10.1021/jm000170m
    528. 528
      Meyers, M. J.; Sun, J.; Carlson, K. E.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen Receptor Subtype-Selective Ligands: Asymmetric Synthesis and Biological Evaluation of Cis- and Trans-5,11-Dialkyl-5,6,11,12- Tetrahydrochrysenes. J. Med. Chem. 1999, 42 (13), 24562468,  DOI: 10.1021/jm990101b
    529. 529
      Meyers, M. J.; Sun, J.; Carlson, K. E.; Marriner, G. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. Estrogen Receptor-β Potency-Selective Ligands: Structure-Activity Relationship Studies of Diarylpropionitriles and Their Acetylene and Polar Analogues. J. Med. Chem. 2001, 44 (24), 42304251,  DOI: 10.1021/jm010254a
    530. 530
      Minutolo, F.; Bertini, S.; Granchi, C.; Marchitiello, T.; Prota, G.; Rapposelli, S.; Tuccinardi, T.; Martinelli, A.; Gunther, J. R.; Carlson, K. E.; Katzenellenbogen, J. A.; Macchia, M. Structural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor β. J. Med. Chem. 2009, 52 (3), 858867,  DOI: 10.1021/jm801458t
    531. 531
      Malamas, M. S.; Manas, E. S.; McDevitt, R. E.; Gunawan, I.; Xu, Z. B.; Collini, M. D.; Miller, C. P.; Dinh, T.; Henderson, R. A.; Keith, J. C.; Harris, H. A. Design and Synthesis of Aryl Diphenolic Azoles as Potent and Selective Estrogen Receptor-β Ligands. J. Med. Chem. 2004, 47 (21), 50215040,  DOI: 10.1021/jm049719y
    532. 532
      Komm, B. S.; Mirkin, S. An Overview of Current and Emerging SERMs. J. Steroid Biochem. Mol. Biol. 2014, 143, 207222,  DOI: 10.1016/j.jsbmb.2014.03.003
    533. 533
      Patel, H. K.; Bihani, T. Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs) in Cancer Treatment. Pharmacol. Ther. 2018, 186, 124,  DOI: 10.1016/j.pharmthera.2017.12.012
    534. 534
      Henke, B. R.; Drewry, D. H.; Jones, S. A.; Stewart, E. L.; Weaver, S. L.; Wiethe, R. W. 2-Amino-4,6-Diarylpyridines as Novel Ligands for the Estrogen Receptor. Bioorg. Med. Chem. Lett. 2001, 11 (14), 19391942,  DOI: 10.1016/S0960-894X(01)00321-3
    535. 535
      Renaud, J.; Bischoff, S. F.; Buhl, T.; Floersheim, P.; Fournier, B.; Geiser, M.; Halleux, C.; Kallen, J.; Keller, H.; Ramage, P. Selective Estrogen Receptor Modulators with Conformationally Restricted Side Chains. Synthesis and Structure-Activity Relationship of ERα-Selective Tetrahydroisoquinoline Ligands. J. Med. Chem. 2005, 48 (2), 364379,  DOI: 10.1021/jm040858p
    536. 536
      Hill, R. A.; Kouremenos, K.; Tull, D.; Maggi, A.; Schroeder, A.; Gibbons, A.; Kulkarni, J.; Sundram, S.; Du, X. Bazedoxifene – a Promising Brain Active SERM That Crosses the Blood Brain Barrier and Enhances Spatial Memory. Psychoneuroendocrinology 2020, 121, 104830,  DOI: 10.1016/j.psyneuen.2020.104830
    537. 537
      Wakeling, A. E.; Dukes, M.; Bowler, J. A Potent Specific Pure Antiestrogen with Clinical Potential. Cancer Res. 1991, 51 (15), 38673873
    538. 538
      Garner, F.; Shomali, M.; Paquin, D.; Lyttle, C. R.; Hattersley, G. RAD1901: A Novel, Orally Bioavailable Selective Estrogen Receptor Degrader That Demonstrates Antitumor Activity in Breast Cancer Xenograft Models. Anti-Cancer Drugs 2015, 26 (9), 948956,  DOI: 10.1097/CAD.0000000000000271
    539. 539
      Conlan, M. G.; de Vries, E. F. J.; Glaudemans, A.; Wang, Y.; Troy, S. Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women. Eur. J. Drug Metab. Pharmacokinet. 2020, 45 (5), 675689,  DOI: 10.1007/s13318-020-00635-3

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

STEP 1:
Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

MENDELEY PAIRING EXPIRED
Your Mendeley pairing has expired. Please reconnect

This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy.

CONTINUE